A decade of pyridine-containing heterocycles in US FDA approved drugs: a medicinal chemistry-based analysis

Abstract

Heterocyclic scaffolds, particularly, pyridine-containing azaheterocycles, constitute a major part of the drugs approved in the past decade. In the present review, we explored the pyridine ring part of US FDA-approved small molecules (2014–2023). The analysis of the approved drugs bearing a pyridine ring revealed that a total of 54 drugs were approved. Among them, the significant number comprised the anticancer category (18 drugs, 33%), followed by drugs affecting the CNS system (11 drugs, 20%), which include drugs to treat migraines, Parkinsonism disorders, chemotherapeutic-induced nausea, insomnia, and ADHD or as CNS-acting analgesics or sedatives. Next, six drugs (11%) were also approved to treat rare conditions, followed by five drugs that affect the hematopoietic system. The analysis also revealed that drug approval was granted for antibiotics, antivirals, and antifungals, including drugs for the treatment of tropical and sub-tropical diseases. Primary drug targets explored were kinases, and the major metabolizing enzyme was CYP3A4. Further analysis of formulation types revealed that 50% of the approved drugs were tablets, followed by 17% capsules and 15% injections. Elemental analysis showed that most approved drugs contained sulfur, while fluorine was noted in 32 compounds. Therefore, the present review is a concerted effort to cover drugs bearing pyridine rings approved in the last decade and provide thorough discussion and commentary on their pharmacokinetics and pharmacodynamics aspects. Furthermore, in-depth structural and elemental analyses were explored, thus providing comprehensive guidance for medicinal chemists and scientists working in allied science domains.

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1. Introduction

The word ‘pyridine’ is derived from the Greek word “pyr”, meaning fire, and “idine”, meaning aromatic bases, as per the Hantzsch–Widman nomenclature.¹ A pyridine scaffold was isolated from the alkaloid picoline in the study by Anderson and group in 1846 for the first time. However, it took over 20 years for its structure to be elucidated by Wilhelm Korner and James Dewar in 1869 and 1871, respectively.^2,3 Chemically, pyridine is a basic heterocyclic aromatic organic compound with the chemical formula C₅H₅N and a molecular weight of 79.11 g mol⁻¹. Structurally (Fig. 1A), it resembles benzene (Fig. 1B) with a six-membered ring structure, whereby one methine group, i.e., =C–H–, is replaced by a nitrogen (–N) atom, which endows it with basicity and polarity.⁴ Furthermore, its overall structure is planar, and it is miscible with water and most organic solvents.

Fig. 1 Electrostatic potential map of (A) pyridine and (B) benzene and their brief chemical analysis.

The –N atom of pyridine makes it a unique and crucial heterocyclic compound in both organic and medicinal chemistry.⁵ This available –N atom possesses a non-bonding electron pair, which participates in hydrogen bonding with druggable receptors and immensely enhances the pharmacokinetic properties of drugs. As per reports, the pyridine nucleus has afforded 7000 existing drug candidates with medicinally important attributes.^1,6 Essential drugs possessing a pyridine core ring include esomeprazole (proton pump inhibitor (PPI)), amlodipine (calcium channel blocker), imatinib (kinase inhibitor), and atazanavir (antiviral).⁷ Besides, pyridine-containing derivatives are an integral part of phytochemicals, including nicotinic acid, nicotinamide, nornicotine, anabasine, trigonelline, and pyridoxine.⁸ The chemical structures of these pyridine-containing derivatives are illustrated in Fig. 2.

Fig. 2 Chemical structures of pyridine-containing drugs and other medicinally essential derivatives.

It is not always true that drug discovery is serendipitous, where the use of a heterocyclic functionality or ring system is not a random choice.^9,10 The selection is strictly based on their key attributes and potential to alter the physicochemical parameters or efficacy outcomes of a drug molecule.¹¹ Amongst the heterocyclic compounds, flat aromatic heterocyclics such as pyridine are considered in the medicinal chemist toolbox owing to their versatility, easy functionalization, and encouraged chemical diversity.^12,13 Moreover, the analysis in the recently published report by Marshall and group revealed (Fig. 3) that among the aza heterocycles, which are part of almost 80% of approved drugs, the pyridine ring (54 drugs) is present in the highest frequency. This is followed by piperidine (40 drugs), pyrrolidine (40 drugs), piperazine (36 drugs), pyrimidine (25 drugs), indole (21 drugs), pyrazole (20 drugs), imidazole (18 drugs), morpholine (13), and benzimidazole (10).^14,15

Fig. 3 Share of top 10 aza-heterocyclics in drug discovery leading to US FDA approval.

Thus, this review highlights the medicinal importance of these versatile pharmacophores systems in the drugs approved in the last decade. We summarize the information on their pharmacological attributes and key pharmacokinetic parameters, including information on the metabolism, clearance, dosage form, major druggable targets, and mechanistic insights. Besides, we focus on thoroughly analyzing their therapeutic area and pharmacophoric diversity, including their structural, functional, and elemental diversity. A thorough investigation of the chemical spacing parameters of approved pyridine-containing drugs compared to approved drugs belonging to diverse heterocycles in the last five years is also presented. This review is expected to enrich the understanding of the medicinal chemistry aspect of these versatile pharmacophores and provide guidance for the medicinal and allied science community.

2. Pyridine as a versatile azaheterocycle in medicinal chemistry and its synthetic strategies

Pyridine is a versatile pharmacophore in medicinal chemistry owing to its various vital assets, especially the plethora of biological activities exhibited by this scaffold.¹⁶ Pyridine-based drugs have been reported to have diverse biological attributes, which include their use as antitubercular drugs (isoniazid), anticancer (abiraterone), antimalarial (enpiroline), respiratory stimulants (nikethamide), myasthenia gravis (pyridostigmine), antiulcer (omeprazole), and anti-Alzheimer's (tacrine).^17,18 Another asset is the ease of the chemical modifiability of the pyridine ring. The pyridine ring is easily substituted at various sites to allow diverse chemical spacing parameters with tailored biological activities. Modifications in the ring system are achieved mainly through nucleophilic substitution (C2 and C4 are primary, while C6 is lesser known).¹⁹ The electron-withdrawing effect of the nitrogen atom makes the attached carbons more electrophilic, thus improving the feasibility of the nucleophile to attack. However, due to a similar reason, the pyridine ring is less susceptible to electrophilic substitution (C3 position) than benzene.²⁰

Nevertheless, the electrophilic reaction susceptibility is improved by forming pyridine-N-oxide given that pyridines are susceptible to oxidation. Besides, pyridine also possesses metalation properties and serves as a ligand in metal complexes formed by N-atom coordination. The typical reaction site for pyridine leading to its chemical diversification is shown in Fig. 4.

Fig. 4 Typical structure of pyridine showing carbon numbering, the influence of its nitrogen atom in inducing charge disparity or polarity to the ring, and the major reaction sites available in the pyridine ring for substitution.

Besides, the pyridine core is engaged in vital biological interactions with receptor sites. Apart from H-bonding, the pyridine ring can engage in π–π stacking interactions and chelation with metal ions or prosthetic groups within biological targets, thus simultaneously enhancing the binding affinity and specificity.²¹ Further, considering their pharmacokinetics properties, pyridine drugs are known to improve the physiochemical aspects of native drugs (Scheme 1). The pyridine motifs are known to improve the (a) metabolic stability, (b) permeability, (c) potency, and (d) binding of drugs. The utility of pyridine was observed in SAR studies for the improvement of biological activity of compounds, wherein Vanotti et al. reported potential Cdc7 inhibitors in which the replacement of the phenyl ring (A) with pyridine (B) resulted in an improvement in biological potency by >500 times.²² In another study on the utility of pyridine for the improvement of metabolic stability, Zheng et al. developed nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. During the establishment of SAR, it was observed that the replacement of the terminal phenyl ring of C with a pyridine ring (D) resulted in an improvement in metabolic stability by 160-fold.²³ Another application of the pyridine moiety is improving cellular permeability. Hong et al. reported tricyclic thiazolopyridines as allosteric modulators of glutamate receptor 4, in which E, possessing a terminal pyridine ring, was found to have more than 190-fold cellular permeability compared to its corresponding phenyl derivative F.²⁴ Similarly, the role of pyridine in fixing protein binding issues at target proteins has also established. Huang et al. reported the preparation of mGluR5 allosteric modulator oxazolidinones, in which the introduction of an additional pyridine ring (H) resolved the protein binding problem and displayed a 35-fold better protein binding affinity.²⁵ In another study by Bryan and group, in their quest to develop N-substituted azaindoles as Cdc7 kinase inhibitors, they found that the replacement of the benzene ring of benzindole (I) with azaindole (J) led to more potent and metabolically stable Cdc7 inhibitors.²⁶ In their quest to develop new human cytomegalovirus immediate-early 2 proteins, Massari and group performed structural modification of a WC5 analogue (K) and observed that the replacement of the benzene ring of the quinoline moiety with pyridine resulted in a more potent and selective molecule as an anti-HCMV agent, L.²⁷

Scheme 1 Some examples showcasing the utility of pyridine motifs in improving the metabolic stability, permeability, potency, and binding of the parent drug.

Besides, we also analysed the molecular descriptors of benzene and pyridine. Their molecular descriptors influence their ligand interaction, selectivity, and reactivity within the biological receptor. These parameters are evaluated using Koopman's theorem,²⁸ which considers the energy gap between the HOMO–LUMO and global reactivity descriptors.²⁹ The present comparative analysis between benzene and pyridine (Table 1) reveals that pyridine possesses a lower (more negative) HOMO and LUMO in comparison to benzene. This indicates that pyridine is more likely to accept electrons than donate them, thus improving their reactivities within biological receptors. Regarding ionization energy, pyridine was again found to possess a higher ionization energy, making it more reactive as an electrophile. Next, pyridine was also found to have a more negative chemical potential (μ). This is a crucial property that can be utilized in designing leads, where the interacting amino acids have positively charged or electron-deficient sites. In the case of chemical hardness (η), benzene is harder (more stable) than pyridine. The lower hardness of pyridine indicates that it offers greater flexibility with the receptor for addition interactions. Due to these properties, compared to benzene, pyridine is a more reactive and polar moiety with the potential to improve the binding specificity and strength within the receptor system. Additionally, the N atom of pyridine can be involved in H bonding under physiological conditions, making it a versatile core ring for the medicinal chemist toolbox.

Table 1 Analysis of the molecular descriptors of benzene and pyridine

Entity	HOMO	LUMO	Ionization energy	Electron affinity	Electronegativity (χ) = (I + A)/2	Chemical potential (μ)	Chemical hardness (η) = (I − A)/2	Chemical softness	Electrophilicity index
Benzene	−7.0785	−0.489	7.079	0.489	3.784	−3.784	3.295	0.152	2.173
Pyridine	−7.2246	−1.3374	7.225	1.337	4.281	−4.281	2.944	0.170	3.113

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2.1. Synthetic strategies

After the first isolation of pyridine in 1846 by Anderson, a Scottish chemist, as a by-product, its first synthesis was reported in 1876 by Ramsay and group (Scheme 2A).³⁰ They prepared pyridine by mixing acetylene (1) and hydrogen cyanide (2) under red-hot settings. This was the first heteroaromatic compound to be synthesized in that century. However, the first major synthetic report is the classical Hantzsch pyridine synthesis reaction published in 1881 by Arthur Hantzsch.³¹ It proceeds by reacting a mixture of acetoacetate or other β-keto acid (3, 2 mols) with an aldehyde (4) containing alpha protons (1 mol) and ammonia (5, 1 mol) (Scheme 2B).

Scheme 2 Traditional methods for the synthesis of pyridine.

Modern-day chemists synthesize this versatile ring using numerous synthetic methodologies. Mehmood et al. reported the one-pot transition metal-free synthesis of 3,4-diaryl-pyridine derivatives via the reaction of aromatic terminal alkynes (6) with benzamides (7) in the presence of Cs₂CO₃. The mechanistic studies revealed a formal [2 + 2 + 1 + 1] cyclo-condensation reaction with three alkynes (2 alkynes providing two carbons each and one alkyne providing one carbon) with one benzamide molecule (providing only nitrogen) to give 3,4-diaryl pyridine derivatives.³² The developed synthetic protocol displayed the efficient application of alkynes and benzamide moieties in the synthesis of pyridine but unfortunately, in some cases, an average yield was observed. In their previous work, the same research group reported the palladium-catalyzed one-pot synthesis of 2,4,6-triaryl pyridines via the cyclo-condensation of aromatic terminal alkynes (6), benzaldehydes (8) and ammonium bisfluoride (9) via oxidation in the presence of tert-butyl peroxide (TBP).³³ Bai et al. reported the synthesis of 2,4-diaryl pyridines via a four-component one-pot synthesis using acetophenones (10), ammonium acetate (11), and DMF (12) catalyzed by RuCl₃ under atmospheric oxygen. DMF provided one carbon (C6) for the cyclization of the ring, while ammonium acetate acted as the nitrogen source.³⁴ This method utilized acetophenone as the starting material, which enhanced the structural diversification for the synthesis of pyridine derivatives with the presence of a large pool of acetophenones. However, the application of the RuCl₃ catalyst increases the cost of this synthetic protocol in comparison to earlier reported methods using simple metal-free basic conditions. Xi et al. transformed various acetophenones (13) into 2-aryl pyridines by reacting with 1,3-diaminopropane (14). Copper catalyzed this electronic transformation in the presence of tosyl sulfonic acid under aerobic conditions.³⁵ Similar to the above-mentioned method, it also involved the application of a metal catalyst but given that copper catalysts are comparatively cheaper to other transition-metal catalysts, this method becomes more feasible. Wang et al. performed a nitrogen insertion technique for the synthesis of aryl-substituted pyridines. Arylcycloalkenes (15) were reacted with trimethylsilyl azide (16) in the presence of Co(acac)₂, DPEphos, and NH₄OAc under aerobic conditions for skeletal editing to yield pyridine derivatives.³⁶ This synthetic protocol provides a unique application for the insertion of nitrogen in existing ring structures. However, the utilization of multiple reagents decreases the atom economy of the reaction, making it an unacceptable protocol in the modern era of green synthetic protocols. Zhang et al. performed biomimetic aza-6π electrocyclization to synthesize 3,4-disubstituted pyridines under visible light conditions. In this synthetic protocol, cinnamaldehyde (17) was reacted with propargyl amines (18) in the presence of DBU catalyzed by visible light (purple-red LEDs). The developed protocol demonstrated wide functional group tolerance and high efficacy under metal and oxidant-free conditions.³⁷ The light activation, metal-free and oxidant-free conditions are the key features of this synthetic protocol. Furthermore, the availability of broad-spectrum picolinaldehydes presents a wide scope for structural diversity with wide functional group tolerance. Huang et al. performed iodine- and triethylamine-triggered coupling of oximes (19) and cinnamaldehydes (20) to synthesize 2-aryl pyridine derivatives via a radical pathway. This metal-free protocol demonstrated high functional group diversity.³⁸ This method established a protocol for the transition metal-free synthesis of multi-substituted pyridines with a wide scope of functional groups with larger pool of structural diversity in cinnamaldehydes and oximes. High yields (up to 92%) add another feature to this synthetic protocol. In another study, Wang et al. performed the [1,3] rearrangement of γ,δ-alkynyl oximes (21) in the presence of potassium carbonate (K₂CO₃) to form pyridine derivatives.³⁹ This is a rearrangement reaction, followed by cyclization in the presence of a simple base without any metal catalyst. The key features of this synthetic protocol are its simple, mild and nontoxic conditions. All the discussed methodologies are compiled in Scheme 3.

Scheme 3 General methods for the synthesis of pyridine and its derivatives.

3. Comparative analysis of the pyridine pharmacophore in US FDA drugs approved between 2014–2023

The analysis of the approved drugs bearing a pyridine ring revealed (Fig. 5) that a total of 54 drugs received approval. Among them, the significant number is in the anticancer category (18 drugs, 33%), followed by drugs affecting the CNS system (11 drugs, 20%), which include drugs to treat migraine, Parkinsonism disorders, chemotherapeutic-induced nausea, insomnia, and ADHD, or as CNS-acting analgesics or sedatives. Next, 6 drugs (11%) were approved to treat rare conditions, followed by 5 drugs that affect the hematopoietic system. The analysis also revealed that drug approval was also granted for antibiotics, antivirals, and antifungals, including drugs to treat tropical and sub-tropical diseases. One drug each was also approved for treating glaucoma, kidney disease, and keratosis. Besides, three contrast/imaging agents were also approved according to our analysis. Thus, to discuss the approved drugs in detail, we classified them into three categories, as follows: a) anticancer, b) other categories, and c) approved contrast/imaging agents. Each subsection summarizes the information on the drugs, including their pharmacodynamics and physiochemical parameters, followed by a detailed analysis of their medicinal chemistry.

Fig. 5 Pie chart showing the percentage share of approved drugs in various pharmacological classes of drugs bearing a pyridine ring.

3.1. Analysis of the approved anticancer agents bearing a pyridine ring

The analysis led to the conclusion that 33% (18 drugs) of the total approvals of pyridine-containing drugs were in the anticancer category. The approved drugs in the anticancer category are compiled in Table 2. This table presents a comprehensive summary of the approved drugs, mechanisms of action, their anticancer druggable targets and type of cancer they are indicated against, and their vital pharmacokinetic parameters.^38,40 The thorough analysis revealed that the approved drugs are not only used for treating the primary types of cancer, including lung cancer, breast cancer, non-Hodgkin lymphoma (NHL), prostate cancer, non-small cell lung cancer, skin cancer, and leukemia.^41,42 According to the Cancer Statistics 2024, the top forms of cancer include lung and bronchus cancer, followed by breast cancer, pancreatic cancer, colon and rectum cancer, and many more. It is also estimated that cancer will kill 611 720 people in America in 2024, causing roughly 1680 deaths per day.⁴³ To combat this, new strides are being taken to develop new therapeutic regimens that are effective against cancer.^44,45 The current analysis of pyridine-containing drugs approved in the last decade revealed that among them, the majority of the drugs were found to target kinases. Kinases are enzymes associated with the transfer of high-energy phosphate groups, growth and numerous critical cellular processes.^46,47 The crucial processes involve cell cycle regulation, proliferation, cellular catabolism, cell survival, and apoptosis. The kinases are frequently seen to be overexpressed in cancer, leading to uncontrolled cell division and proliferation.⁴⁸ Among the 540 kinases reported to date, the majority of kinases that are found overexpressed in cancer include those belonging to the family of receptor tyrosine kinases (RTKs), which are located on the cell surface (e.g., EGFR, HER2, and VEGFR).^49,50 The second class includes serine/threonine kinases, which regulate the key signalling pathways, including the MAPK and PI3K pathways (e.g., CDKs, MEK, and AKT).⁵¹ All these kinases share similar peculiarities, where all are transmembrane receptors having two extracellular and intracellular binding domains. The extracellular domains are associated with the binding of natural ligands (e.g., amphiregulin or EGF with EGFR), which initiate the process of dimerization (homo or heterodimerization), also called pre-activation. The extracellular domain is targeted by monoclonal antibodies ‘mabs’ (trastuzumab, pertuzumab, bevacizumab, etc.). The mabs compete with the natural ligands of the kinases and hamper their binding.⁵²

Table 2 Anticancer drugs possessing a pyridine ring system and their pharmacodynamics and physiochemical attributes

S no.	Drug name (brand name) (approval year)	Category	Biological target	Mechanism	Indication dosage type and route	Half-life (in h) and excretion	Phase 1 metabolism	DB ID
1.	Abemaciclib (Verzenio) 2017	Serine threonine kinase inhibitor	Cyclin-dependent kinase (CDK) 4/6	Kinase inhibitor works by inhibiting the binding of ATP to the catalytic domain of the kinase, thereby inhibiting phosphorylation, which results in cell cycle arrest at the G1 phase	Breast cancer tablet, film-coated; oral route	18.3 h; 81% metabolized drug is excreted in feces, while 3% via urine	CYP3A4; forms two major metabolites, N-desethylabemaciclib and hydroxyabemaciclib	DB12001
2.	Palbociclib (Ibrance) 2015				Breast cancer tablet, film-coated; capsule; oral route	29 h; majorly excreted via feces as metabolites while only 17.5% excreted via urine	Cytochrome P450 isoenzyme 3A and sulfotransferase 2A1	DB09073
							Sulfonation, oxidation, and glucuronidation
3.	Ribociclib (Kisqali) 2017				Gastrointestinal stromal tumors tablet, film-coated; oral route	32.6 h	Not available	DB11730
4.	Trilaciclib (Cosela) 2021				Myeloprotection injection; IV route	14 h; 79.1% excreted via feces and 14% via urine	Extensively metabolized but yet to be established	DB15442
5.	Acalabrutinib (Calquence) 2017	Tyrosine kinase inhibitor	Bruton's tyrosine kinase (BTK) inhibitor	Acalabrutinib and its metabolite ACP-5862 bind covalently to Cys481 residue at the active site of BTK and block its enzymatic action	Non-Hodgkin lymphoma (NHL); tablet, capsule, coated; oral route	0.9 h; 84% of dose excreted in feces and 12% in urine	CYP3A; major observed metabolite is ACP-5862	DB11703
6.	Asciminib (Scemblix) 2021	Tyrosine kinase inhibitor	Inhibitor of ABL1 kinase activity of the BCR-ABL1 fusion protein	Allosterically inhibits the BCR-ABL1 tyrosine kinase by binding to myristoyl pocket of ABL1	Chronic myeloid leukemia tablet, film-coated; oral route	5.5–9 h; 80% of dose excreted in feces and 11% in urine	None to negligible metabolism	DB12597
7.	Neratinib (Nerlynx) 2017		EGFR, HER2 and HER4 inhibitor	Binds to EGFR, HER2, and HER4, irreversibly and blocks the phosphorylation of tyrosine residues, leading to the blockage of MAPK/AKT signalling	Breast cancer tablet, film-coated; oral route	7–17 h; 97.1% excreted via feces and 1.13% via urine	CYP3A4 and MAO-mediated metabolism	DB11828
							Four major metabolites include M3 (15%), M6 (33%), M7 (22%), and M11 (4%)
8.	Pexidartinib (Turalio) 2019		Colony-stimulating factor (CSF1)/CSF1 receptor pathway inhibitor	Interacts with juxtamembrane region of CSF1R and prevents the binding of CSF1 and ATP. It leads to blockage of ligand-induced autophosphorylation and blocks the tumor growth and cell proliferation	Tenosynovial giant cell tumors (TGCT) capsule; oral route	16.6 h; 65% excreted via feces and 27% via urine	CYP3A4 and UGT1A4-mediated metabolism with N-glucuronide as major metabolite	DB12978
9.	Pralsetinib (Gavreto) 2020		RET tyrosine kinase receptor (RTK) inhibitor	Inhibits the RET tyrosine kinase receptors and prevents chromosomal dimerization and subsequent autophosphorylation, leading to the downregulation of downstream signalling of tumor invasion and proliferation	Thyroid cancer capsule; oral route	14.7–22.2 h; 73% excreted via feces and 6% via urine	CYP3A4, CYP2D6 and CYP1A2	DB15822
							Oxidation to M453, M531, and M549b metabolites
10.	Selpercatinib (Retevmo) 2020		RET tyrosine kinase receptor (RTK) inhibitor	Inhibits the RET tyrosine kinase receptors and prevents chromosomal dimerization and subsequent autophosphorylation, leading to the downregulation of downstream signalling of tumor invasion and proliferation	Solid tumors (RET) tablet and capsule; oral route	32 h; 69% excreted via urine and 24% via urine	CYP3A4-mediated metabolism	DB15685
11.	Ripretinib (Qinlock) 2020		Wild-type and mutant platelet-derived growth factor receptor A (PDGFRA) and KIT inhibitor	Inhibits KIT (with mutations on exons 9, 11, 13, 14, 17, and 18) and PDGFRA (with mutations on exons 12, 14, and 18) and turns off these kinases to prevent dysregulated cell proliferation	Gastrointestinal stromal tumors tablet; oral route	14.8 h; 34% excreted via feces and 0.2% via urine	CYP3A with role of CYP2D6 and CYP2E1 major active metabolite is DP-5439	DB14840
12.	Alpelisib (Piqray, Vijoice) 2019	Kinase inhibitor (lipid kinase family)	Phosphatidylinositol 3-kinase (PI3K) p110α subunit inhibitor	It inhibits PI3K with high selectivity for the p110α subunit and prevents cell proliferation and tumor growth	Breast cancer tablet, film-coated; oral route	8–9 h; 36% unchanged and 32% as BZG791 in feces, while 2% unchanged and 7.1% as BZG791 in urine	CYP3A4; M4 or BZG791 is the only metabolite, identified and complete metabolic profile yet to be established	DB12015
13.	Lorlatinib (Lorbrena) 2018	Tyrosine kinase inhibitor	Anaplastic lymphoma tyrosine kinase inhibitor (ALK-TKI)	Inhibits the ALK kinase together with other kinase receptor genes such as ACK, FAK, FAK2, FER, FPS, TRKA, TRKB, TRKC, TYK1, and ROS1	Non-small cell lung cancer tablet, film coated; oral route	24 h; 48% excreted in urine and 41% via feces	CYP3A4 and UGT1A4-mediated metabolism	DB12130
							Benzoic acid derivative followed by oxidative cleavage
14.	Apalutamide (Erleada) 2018	Androgen receptor (AR) antagonist	Androgen receptors (ligand binding domain blocker)	Blocks the AR nuclear translocation via binding to the ligand-binding domain of androgen receptors	Prostate cancer tablet, film coated; oral route	72 h; 65% excreted via urine and 24% via feces	CYP2C8 and CYP3A4; N-desmethyl apalutamide and M4 apalutamide metabolite	DB11901
15.	Enasidenib (Idhifa) 2017	Dehydrogenase inhibitor	Isocitrate dehydrogenase-2 inhibitor	Inhibits the wild-type isocitrate dehydrogenase-2 in relapsed or refractory acute myeloid leukaemia and abrupt cellular processes	Myeloma tablet, film-coated; oral route	7.9 days; 89% excreted via urine and 11% via feces	Multiple cytochrome P450 (CYP) enzyme-mediated metabolism; N-dealkylated metabolite	DB13874
16.	Ivosidenib (Tibsovo) 2018	Dehydrogenase inhibitor	Isocitrate dehydrogenase-1 inhibitor	Inhibits the mutant isocitrate dehydrogenase-1 than wild-type targeting mutations R132, with R132H and R132C	Acute myeloid leukemia tablet, film coated; oral route	98 h; 77% excreted via feces (67% unchanged), while 17% excreted via urine	CYP3A4-mediated oxidation	DB14568
				Decreases level of D-2HG			N-Alkylation and hydrolysis
				Inhibits histone demethylases
17.	Sonidegib (Odomzo) 2015	Hedgehog signaling pathway inhibitor	Smoothened (Smo) regulator inhibitor	Inhibits the smoothened (Smo) regulator, leading to the downregulation of the Hedgehog pathway and suppression of tumor growth	Skin cancer capsule; oral route	28 days; 70% excreted via feces and 30% excreted via urine	CYP3A4-mediated oxidation and amide hydrolysis	DB09143
18.	Sotorasib (Lumakras) 2021	Kirsten rat sarcoma virus (KRAS) inhibitor	KRAS G12C mutation inhibitor	Binds to the cysteine residue of KRAS (G12C mutant) and makes it inactive for treatment of NSCLC. This residue is absent in normal KRAS	Lung cancer; tablet, film coated; oral route	5.5 h; 74% excreted via feces and 6% via urine	CYP3As	DB15569

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Once the natural kinase ligand is bound, the receptor undergoes dimerization, leading to a conformational change in the intracellular domain of the receptor. The intracellular domain contains the catalytic domain, where ATP binds and induces phosphorylation in the amino acid residues (tyrosine in the case of EGFR, serine in case of CDKs, etc.) and initiates the signalling cascade via their downstream targets, leading to gene expression, cell division, and proliferation.⁵³ The majority of the small molecule kinase inhibitors abbreviated as ‘nibs’ (e.g., erlotinib, gefitinib, ruxolitinib, and sunitinib) compete or hamper ATP binding within the catalytic domain, leading to kinase inhibition.^54,55 This induces apoptosis in cancer cells, halting their division, and consequently proliferation.^56,57 In the present investigation, we found that 13 drugs out of a total of 18 anticancer drugs directly inhibit kinases. The important kinases that are affected belong to the class of tyrosine kinases (8 drugs).^58,59 The essential kinases that are affected in this category are Bruton's tyrosine kinase (BTK) (acalabrutinib), ABL1 kinase (asciminib), EGFR and HER2 (neratinib and pexidartinib, respectively), RET tyrosine kinase (pralsetinib and selpercatinib), PDGFR and KIT (ripretinib), and ALK kinase (lorlatinib). This was followed by the serine–threonine kinases, particularly the cyclin-dependent kinase (CDK) 4/6, where four anticancer drugs were approved (abemaciclib, palbociclib, ribociclib, and trilaciclib). This was followed by one approval under lipid kinase, specifically PI3K (alpelisib). Besides this, one drug, sonidegib, was found to interfere with the Hedgehog signalling pathway and found to inhibit the smoothened (Smo) regulator, leading to the downregulation of the Hedgehog pathway, and suppressing tumour growth.

Besides this, two drugs were approved as dehydrogenase inhibitors (enasidenib and ivosidenib). The dehydrogenase in cancer assists in the metabolic reprogramming of cancer cells to support their growth division and survival. Dehydrogenases maintain the balance of NAD⁺/NADH, thus allowing redox homeostasis, and consequently in energy production. Besides this, some dehydrogenases, including isocitrate dehydrogenase (IDH), are also associated with regulating oxidative stress by regulating ROS. Further mutation in IDH isoforms leads to the production of 2-hydroxyglutarate, which is an oncometabolite associated with tumour survival and prognosis. The drugs approved in this category are reported to inhibit the mutant IDH isoforms selectively, thus halting cancer progression.

Further, 1 drug, apalutamide, was approved and found to target the androgen receptor (AR) and inhibit it. This drug has found utility in treating prostate cancer, where androgen and AR are both highly expressed. It blocks AR nuclear translocation by binding to the ligand-binding domain of androgen receptors. Lastly, 1 drug, sotorasib, was found to be a Kirsten rat sarcoma virus (KRAS) inhibitor. KRAS is an oncogene that is vital in regulating cell division and proliferation. The drug is reported to bind the cysteine residue of KRAS (G12C mutant) and make it inactive for the treatment of NSCLC. This residue is absent in normal KRAS.

Nevertheless, the analysis also revealed that 3 drugs out of 18 are recognized for their therapeutic outcomes in numerous rare forms of cancer including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and tenosynovial giant cell tumours (TGCT). CML is a type of blood cancer that affects the old population and leads to the abnormal growth of white blood cells, also referred to as myeloid cells.⁶⁰ The drug approved in this category is asciminib. This drug is a tyrosine kinase inhibitor, which his associated with inhibiting the ABL1 kinase activity of the BCR-ABL1 fusion protein. It is reported to allosterically inhibit the BCR-ABL1 tyrosine kinase by binding to the myristoyl pocket of ABL1.⁶¹ Presently, AML is a rapidly growing cancer in the youth and old populations.⁶² It affects the bone marrow, particularly the myeloid line of blood cells, which causes the abnormal growth of WBCs. The drug approved to cure AML is ivosidenib. This drug is reported to irreversibly inhibit dehydrogenase, particularly mutant IDH1 enzyme, which results in a decrease in oncometabolite, i.e., 2-hydroxyglutarate (2-HG).⁶³ Lastly, although TGCT is a benign form of cancer, if left untreated, it can localize to the tendon sheaths, causing joint swelling, pain, and tenderness in the affected area.⁶⁴ This causes the problem of voluntary motion of joints and joint stiffness. The approved drug to treat TGCT is pexidartinib. This drug inhibits the pathway mediated by the colony-stimulating factor (CSF1) by interacting at the juxtamembrane region of CSF1R. The binding prevents the binding of CSF1 and ATP, leading to the blockage of ligand-induced autophosphorylation and prevention of tumour growth and cell proliferation.⁶⁵

The chemical structures of the reported anticancer drugs are illustrated in Fig. 6.

Fig. 6 Chemical structures of the reported anticancer drugs bearing a pyridine ring.

3.2. Analysis of the approved drugs (other than anticancer) bearing a pyridine ring

The analysis in this category revealed that 33 drugs out of the 54 approved are in this category. A deeper analysis revealed that among the approved drugs, most of the drugs are approved for the CNS system (11 drugs), including drugs to treat migraines, Parkinsonism disorders, chemotherapeutic-induced nausea, insomnia, and ADHD, or as CNS-acting analgesics or sedatives. Next, 6 drugs were approved to treat rare conditions, followed by 5 drugs that affect the hematopoietic system. A thorough compilation of these drugs, including their name, indication, biological target, mechanism, dosage, route of administration, and data on the half-life, excretion, and metabolism is presented in Table 3.^38,40 The analysis revealed that 4 drugs (atogepant, rimegepant, ubrogepant, and lasmiditan) were approved for the treatment of migraines.

Table 3 Approved drugs other than the anticancer category possessing a pyridine ring system and their pharmacodynamics and physiochemical attributes

S no.	Drug name (brand name) (approval year)	Indication	Biological target	Mechanism	Dosage type and route	Half-life (in h) and excretion	Phase 1 metabolism	DB ID
1.	Abametapir (Xeglyze) 2020	Head lice	Louse metalloproteinases	Metalloproteinase inhibitors specifically in head lice, which prevent the hatching and development of lice eggs	Lotion; topical route	71 h; excretion route not yet established	CYP1A2; metabolized to abametapir hydroxyl, and then to abametapir carboxyl	DB11932
2.	Amifampridine (Firdapse, Ruzurgi) 2018	Lambert–Eaton myasthenic syndrome (LEMS)	Presynaptic acetylcholine voltage-gated potassium channel blockers	Enhances the concentration of acetylcholine at neuromuscular junctions by blocking presynaptic acetylcholine voltage-gated potassium channels and provides symptomatic relief in Lambert–Eaton myasthenic syndrome (LEMS)	Tablet; oral route	3.6–4.2 h; 93% excreted via urine in 24 h, which includes 81% in the form of metabolites	Metabolized by enzyme N-acetyltransferase 2 (NAT2) to give 3-N-acetyl-amifampridine	DB11640
3.	Atogepant (Qulipta) 2021	Migraine	Calcitonin gene-related peptide (CGRP) receptor antagonist	Competitively inhibit the CGRP receptors and inhibit the action of CGRP, which is responsible for intensifying the migraine pain	Tablet; oral route	11 h; 42% excreted in feces, while 5% in urine in unchanged form	CYP3A4; major metabolite is glucuronide conjugate (M23)	DB16098
4.	Rimegepant (Nurtec) 2020					11 h; 78% excreted in feces and 24% in urine	CYP3A4; metabolites not yet identified	DB12457
							77% of drugs is excreted unchanged
5.	Ubrogepant (Ubrelvy) 2019					5–7 h; 42% unchanged excreted in feces and 6% excreted in urine	CYP3A4; metabolised to two inactive glucuronide metabolites	DB15328
6.	Lasmiditan (Reyvow) 2019		5-HT1F agonist	Agonise 5-HT1F receptors and inhibit trigeminal neuronal firing to prevent migraine pain	Tablet, film-coated; oral route	5.7 h; 66% eliminated via metabolism, while only 3% eliminated unchanged via urine	Ketone reduction two primary metabolites are M7 and M18	DB11732
7.	Avatrombopag (Doptelet) 2018	Thrombocytopenia in liver disease	Thrombopoietin receptor (c-Mpl) agonist (TPOR)	Increases the concentration of platelets via stimulation of the TPOR, which further improves the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells	Tablet, film-coated; oral route	19 h; 84% (34% unchanged) excreted in feces, while 6% in urine	CYP2C9 and CYP3A4	DB11995
8.	Betrixaban (BEVYXXA) 2017	Anticoagulant	Factor Xa inhibitor anticoagulant	Inhibits both free and prothrombinase-bound factor Xa, leading to anticoagulant action	Capsule, gelatin-coated; oral route	19–27 h; 85% excreted in feces while 11% in urine	<1% hepatic metabolism	DB12364
9.	Edoxaban (Lixiana, Savaysa) 2015				Tablet, film-coated; oral route	10–14 h; majorly excreted in urine unchanged	CYP3A4, minimal metabolism	DB09075
10.	Delafloxacin (Baxdela) 2017	Antibiotic	DNA gyrase (topoisomerase II) and DNA topoisomerase IV inhibitor	Inhibit the bacterial DNA topoisomerase II and IV and lead to blockage of positive supercoil relaxation and prevent DNA replication	Tablet; oral route	3.7 h; 65% excreted in urine and 28% via feces	<1% via oxidation, undergoes glucuronidation in presence of UDP glucuronosyltransferase 1-1, UDP-glucuronosyltransferase 1-3, and UDP-glucuronosyltransferase 2B15	DB11943
					Injection; IV route
11.	Ozenoxacin (Ozanex) 2017	Antibiotic against impetigo			Cream; topical route	Not studied	None to minimal metabolism on human skin	DB12924
12.	Tedizolid phosphate (Sivextro) 2014	Antibiotic	Ribosomal RNA (rRNA) inhibitor	Inhibits the peptidyltransferase centre (PTC) via binding at A site interacting with 23S rRNA and leads to structural irregularities. It inhibits bacterial protein synthesis	Tablet, film-coated; oral route	12 h; 82% excreted via feces and 18% via urine	Tedizolid is metabolized in the liver to inactive sulfate conjugate without contribution from cytochrome P450 enzymes	DB09042
					Injection; IV route
13.	Elexacaftor (Trikafta) 2019	Cystic fibrosis	Cystic fibrosis transmembrane conductance regulator (CFTR) gene corrector	Modulates CFTR proteins to promote cell surface trafficking for improvement of cell membrane with increased mature CFTR proteins	Tablet, film-coated; oral route	24.7 h; 87.3% excreted in feces and 0.23% in urine	CYP3A4/5, primarily metabolized to M23-ELX	DB15444
14.	Lumacaftor (Orkambi) 2015	Cystic fibrosis	Cystic fibrosis transmembrane conductance regulator (CFTR) gene corrector	Enhances the conformational stability of F508del-CFTR proteins to promote cell surface trafficking for improvement of cell membrane with increased mature CFTR proteins	Tablet, film-coated; oral route	26 h; 51% excreted via feces and 8.6% excreted via urine	Not extensively metabolized, minimal oxidation and glucuronidation	DB09280
15.	Finerenone (Kerendia) 2021	Kidney disease	Mineralocorticoid receptor (MR) antagonist	Antagonizes MR and reduces inflammation and fibrosis	Tablet, film-coated; oral route	17.4 h; majorly excreted via urine as metabolites	CYP3A4 and CYP2C8; metabolised to M1, M2, M3, M4 and M5 metabolites involving oxidation and hydrolysis	DB16165
16.	Fostamatinib (Tavalisse) 2018	Chronic immune thrombocytopenia (ITP)	Tyrosine kinase inhibitor	The active metabolite, R406, binds to the ATP-binding pocket of spleen tyrosine kinase and blocks the signalling cascade	Tablet, film-coated; oral route	15 h; 80% excreted via feces and 20% via urine	Gut alkaline phosphate metabolizes to R406 followed by CYP3A4-mediated oxidation and UGT1A9-mediated glucuronidation	DB12010
17.	Fosnetupitant (Akynzeo) 2018	Chemo-induced nausea and vomiting	P/neurokinin-1 (NK-1) receptor antagonist	The active metabolite, netupitant, competitively blocks the P/NK-1 receptor in CNS and inhibits the binding of tachykinin neuropeptide substance P	Injection in combination with other drugs; IV route	80 h; 70.7% excreted via feces and 3.95% via urine	Prodrug of netupitant and acts as substrate and inhibitor of CYP3A4	DB14019
		Antiemetic
18.	Netupitant (Akynzeo) 2014	Chemo-induced nausea and vomiting	Neurokinin-1 (NK-1) receptor antagonist	Competitively blocks the P/NK-1 receptor in CNS and inhibits binding of tachykinin neuropeptide substance P	Injection in combination with other drugs; IV route; capsule, oral route	96 h; primarily via feces	CYP3A4, CYP2C9 and CYP2D6	DB09048
		Antiemetic					M1 metabolite: desmethyl derivative, M2 metabolite: N-oxide derivative,
							M3 metabolite: OH-methyl derivative
19.	Isavuconazonium (Cresemba) 2015	Antifungal	Lanosterol 14-alpha-demethylase (Erg11p) inhibitor	Active metabolite isavuconazole inhibits the synthesis of ergosterol via inhibition of the P450-dependent Erg11p enzyme and prevents fungal cell membrane synthesis	Capsule, powder; oral route	130 h; 46.1% excretion via feces and 45.5% excretion via urine	Esterase enzymes hydrolyse to isavuconazole	DB06636
							CYP3A4, CYP3A5, and UGT-mediated metabolism
20.	Oteseconazole (Vivjoa) 2022	Antifungal	Lanosterol 14-alpha-demethylase inhibitor	Inhibit the synthesis of ergosterol via inhibition of P450-dependent CYP51 enzyme and prevent fungal cell membrane synthesis	Capsule, powder; oral route	138 days; majorly via feces and bile	No significant metabolism	DB13055
		Against recurrent vulvovaginal candidiasis (RVVC)
21.	Lenacapavir 2022	HIV-AIDS	HIV-1 inhibitor	Inhibits the capsid proteins and blocks the their interaction with CPSF6 and Nup153	Tablet, film coated; oral route	10–12 days; 76% excretion in feces and 1% in urine	CYP3A4- and UGT1A1-mediated metabolism such as N-dealkylation, oxidation, hydrogenation, and glucuronidation	DB15673
				Inhibits viral nuclear entry, viral DNA synthesis, and viral transcription	Injection; subcutaneous route
22.	Lonafarnib (Zokinvy) 2020	Hutchinson–Gilford progeria syndrome (HGPS)	Farnesyl transferase inhibitor	Inhibits farnesyl transferase and leads to reduction of progerin accumulation, slowing down HGPS	Capsule; oral route	4–6 h; 62% excreted via feces and <1% excreted via urine	CYP3A4/5, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1-mediated metabolism	DB06448
							Oxidation followed by dehydration
23.	Leniolisib (Joenja) 2023	Activated phosphoinositide 3-kinase delta syndrome (APDS)	Phosphoinositide 3-kinase-delta inhibitor	Inhibits PI3Kδ via blockage of the p110δ subunit of its binding site	Tablet, film-coated; oral route	7 h; 67% excreted via feces and 25.5% via urine	CYP3A4-mediated oxidative metabolism with small contributions from CYP3A5, CYP1A2 and CYP2D6	DB16217
24.	Lemborexant (Dayvigo) 2019	Insomnia	Dual orexin-1 receptors (OX1R) and orexin-2 receptors (OX2R) antagonist	Competitively antagonizes OX1R and OX2R and blocks the binding of orexin-1 and orexin-2, which suppresses wakefulness leading to sleep	Tablet, film coated; oral route	17–19 h; 57.4% excreted via feces and 29.1% via urine	CYP3A4, major metabolite is M10 having similar activity as the parent molecule	DB11951
							Subsequent metabolism involves CYP3A and CYP2B6
25.	Oliceridine (Olinvyk) 2022	Analgesic	μ-Opioid receptor agonist	As a “biased agonist”, binds to the μ-opioid receptor, leading to activation of the G-protein pathway via minimum phosphorylation of receptors and β-arrestin recruitment	Injection; IV route	1.3–3 h; 70% excreted via urine and 30% via feces	CYP3A4 and CYP2D6	DB14881
							N-Dealkylation, dehydrogenation, and glucuronidation
26.	Omidenepag (Omlonti) 2022	Glaucoma	Prostaglandin E2 (EP2) receptor	Selectively agonizes the EP2 receptors and reduces intraocular pressure by increasing aqueous humor outflow	Solution; ophthalmic route	0.5 h; 83% excreted via feces and 4% via urine	CYP3A4	DB15071
							N-Dealkylation and conjugation metabolites
27.	Opicapone (Ongentys) 2020	Parkinson's disease	Catechol-o-methyltransferase (COMT) inhibitor	Inhibits the COMT enzyme, peripherally and selectively	Capsule; oral route	1–2 h; 70% excreted via feces, 20% exhaled via breathing and 5% via urine	COMT-mediated methylation, reduction, and glutathione conjugation	DB11632
				In combination with L-DOPA and DOPA carboxylase inhibitor, it improves the plasma concentration of L-DOPA for crossing BBB			3-O-Sulphated opicapone
							4-O-Methylated opicapone
28.	Remimazolam (Byfavo) 2020	Sedative	Gamma-aminobutyric acid GABA-A receptors agonist	Benzodiazepine derivatives act by potentiating the inhibitory effect of GABA-A by binding to the benzodiazepine site of receptors and suppress nerve-firing	Injection; IV route	37–53 min; >80% excretion via urine	No hepatic P450 enzyme-mediated metabolism	DB12404
							Hepatic carboxylesterase-1 (CES1) metabolised to inactive CNS7054
29.	Serdexmethylphenidate (Azstarys) 2021	Attention deficit hyperactivity disorder (ADHD)	5HT1A agonist	Dexmethylphenidate (active metabolite) increases the level of dopamine and norepinephrine via inhibition of corresponding monoamine transporters. Other plausible mechanisms include agonism of 5-HT1A receptor, vesicular monoamine transporter-2 (VMAT-2) redistribution, and α2-adrenergic receptor activation	Capsule; oral route	5.7–11.7 h; 62% excreted via urine and 37% in feces	Dexmethylphenidate metabolized by carboxylesterase 1A1 to D-ritalinic acid	DB16629
							Oxidized metabolites
							Trans-esterification
30.	Tirbanibulin (Klisyri) 2020	Actinic keratosis	Dual Src kinase and tubulin inhibitor	Inhibits Src kinase (peptide binding site) and tubulin (colchicine binding site) in fast proliferating cells and prevents cell proliferation, migration, and cell survival	Ointment; topical route	4 h	CYP3A4; inactive metabolites KX2-5036 and KX2-5163	DB06137
31.	Vonoprazan (Voquezna) 2022	Gastric ulcers	Potassium-competitive acid blocker (PCAB)	Inhibits H^+/K^+-ATPase-mediated acid secretion in the stomach by blocking PCA	Tablet; oral route	6.8 h; 67% excreted via urine and 31% via feces	CYP3A4, CYP3A5, CYP2B6, CYP2C19, CYP2C9 and CYP2D6	DB11739
							Inactive conjugated metabolites
32.	Vorapaxar (Zontivity) 2014	Antiplatelet	Protease-activated receptor (PAR-1) inhibitor	Inhibits PAR-1 reversibly, which leads to blockage of thrombin-induced platelet aggregation	Tablet, film-coated; oral route	3–8 days; 91.5% excreted via feces and 8.5% excreted via urine	CYP3A4 and CYP 2 J2	DB09030
							Two major metabolites are M19 and M20
33.	Voxelotor (Oxbryta) 2019	Sickle cell disease	Hemoglobin S (HbS) polymerization inhibitor	Binds to N-terminal valine of the α-chain of hemoglobin reversibly, which improves the oxygenated Hb state and prevents HbS polymerization	Tablet, film-coated; oral route	35.5 h; 62.6% excreted in feces and 35.5% via urine	CYP3A4 and by CYP2C19, CYP2B6, and CYP2C9	DB14975
							Oxidation and reduction

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Migraines, “episode headaches”, are one of the most common disabling CNS disorders with a large number of comorbidities.⁶⁶ They affect more than one billion people each year worldwide, with high prevalence among the young and female population.⁶⁷ In 2016, migraines were the second most common contributor to neurological disorders in disability-adjusted life-years (DALYs) lost, accounting for 16.3%. Based on multiple mechanisms, migraines are associated with several risk factors, such as aging, head injury, stress, medications, lower social status, stress, sleep disturbances, pain syndrome, and pro-inflammatory or pro-thrombotic states.⁶⁸ However, the current medications associated with preventive treatment provide unsatisfactory results against acute single attacks, thus leading to chronicity.^69,70 Among the four approved drugs, 3 drugs, i.e., atogepant, rimegepant, and ubrogepant, are calcitonin gene-related peptide (CGRP) receptor antagonists.^71,72 These drugs competitively inhibit the CGRP receptors and inhibit the action of CGRP, which is responsible for intensifying migraine pain. CGRP activation is otherwise associated with the vasodilation of blood vessels in the brain, causing throbbing pain.⁷³ Besides, this also causes neurogenic inflammation and is associated with pain signal transmission, further precipitating migraine-associated pain. One drug, lasmiditan, has been approved as a serotonin (5-HT) receptor 1F (5-HT1F) agonist. It agonizes the 5-HT1F receptors and inhibits the trigeminal neuronal firing of serotonin to prevent migraine pain.⁷⁴

The other approved drugs affecting CNS include opicapone for treating Parkinson's disease. This drug acts by inhibiting catechol-o-methyltransferase (COMT) peripherally and selectively.⁷⁵ COMT is associated with the metabolism of catecholamines (dopamine) in Parkinsonism.⁷⁶ The metabolism converts dopamine to 3-methoxytyramine (3-MT) and homovanillic acid (HVA), which is then excreted via urine. This replenishes the dopamine levels and overcomes the dopamine deficiency associated with Parkinson's disease.⁷⁷

Further, two drugs, fosnetupitant and netupitant, have been approved for the treatment of chemotherapy-induced nausea and vomiting.⁷⁸ These drugs act as P/neurokinin-1 (NK-1) receptor antagonists and competitively block the P/NK-1 receptor in CNS and inhibit binding of tachykinin neuropeptide substance P. Besides, one drug, lemborexant, has been approved for treating insomnia and acts as a dual inhibitor of dual orexin-1 receptors (OX1R) and orexin-2 receptors (OX2R) antagonist, thus blocking the binding of orexin-1 and orexin-2, which suppresses the wakefulness leading to sleep.⁷⁹ Additionally, one drug is also approved in the sedative category, remimazolam, which is a gamma-aminobutyric acid GABA-A receptor agonist and potentiates the inhibitory effect of GABA-A via binding to the benzodiazepine site of the receptors.⁸⁰ Another drug, serdexmethylphenidate, is approved for the treatment of attention deficit hyperactivity disorder (ADHD). This drug undergoes metabolism for its activation to form dexmethylphenidate, which increases the level of dopamine and norepinephrine via inhibition of the corresponding monoamine transporters.⁸¹ The last drug in this category affecting CNS is oliceridine, which is an analgesic and acts as a biased agonist. It binds to the μ-opioid receptor, activating the G-protein pathway via the minimum phosphorylation of receptors and allowing β-arrestin recruitment.^82,83

Continuing the analysis, particular emphasis has also been placed on approving drugs for treating rare conditions. A total of 6 drugs (out of 33 in this category) was approved to treat rare diseases. These rare diseases include Lambert–Eaton myasthenic syndrome (LEMS), cystic fibrosis, chronic immune thrombocytopenia, Hutchinson–Gilford progeria syndrome, and activated PI3K delta syndrome (APDS).⁸⁴

LEMS (or myasthenic syndrome) is a rare autoimmune disorder characterized by the weakening of limb muscles.⁸⁵ This is owing to the reduction in acetylcholine release from the presynaptic nerve terminal, resulting in antibody development, which primarily targets voltage-gated calcium channels (VGCCs), where the acetylcholine is stored.⁸⁶ The drug approved in this category, amifampridine, is reported to act as a presynaptic acetylcholine voltage-gated potassium channel blocker, enhance the concentration of acetylcholine at neuromuscular junctions via blocking presynaptic acetylcholine VGCCs and provide symptomatic relief in LEMS.⁸⁷ Besides LEMS, elexacaftor and lumacaftor have been approved to treat cystic fibrosis. Cystic fibrosis is a rare but inherited disease, affecting the cells producing mucus, sweat, or digestive juices. The presence of disease makes this fluid highly viscous and sticky. Subsequently, the movement of this fluid results in the clogging of stiffness of the ducts or the passageways of significant organs with symptoms of heavy cough, lung infections, fatty stool, and lean gesture.⁸⁸ The drug in this category affects cystic fibrosis transmembrane conductance regulator (CFTR). This gene corrector modulates CFTR proteins to promote cell surface trafficking and improve cell membranes with increased mature CFTR proteins.⁸⁹ Another rare disease for which a drug is approved is chronic immune thrombocytopenia (ITP). A viral response chiefly triggers ITP and affects the autoimmune system. This leads to the destruction of blood-clotting platelets, allowing poor blood clotting.⁹⁰ Fostamatinib is approved to treat this condition and acts as a tyrosine kinase inhibitor. It gets activated upon metabolism, forming an active metabolite, R406, which binds to the ATP-binding pocket of spleen tyrosine kinase and blocks the signalling cascade. This will reduce autoantibody production against platelets, and the activation of macrophages that destroy the antibody-coated platelets will diminish.⁹¹

Additionally, Hutchinson–Gilford progeria syndrome or progeria is an infrequent genetic disorder that affects children initially in the first two years of their life.⁹² The children show rapid symptoms of dramatic aging, which is characterized by hair loss and slow growth.⁹³ The drug approved in this category is lonafarnib, which acts by inhibiting the farnesyl transferase enzyme, thus reducing progerin accumulation and slowing down HGPS.⁹⁴ Activated PI3K delta syndrome (APDS) is another rare immunodeficiency disease, which is characterized by mutations in either PIK3CD or PIK3R1.⁹⁵ These two genes are essential in the functioning and development of immune cells within the body. Thus, their mutation leads to immune dysfunction including impaired T-cell and B-cell function and abnormality in immune cell growth, which may further lead to enlarged lymph nodes, splenomegaly, hemolytic anaemia, and consequently an increased risk of cancer.⁹⁶ The drug approved in this category is leniolisib, which inhibits PI3Kδ via blockage of the p110δ subunit of the binding site, thus hampering the upregulation of the associated genes in APDS.⁹⁷

Besides, two drugs were also approved to treat the conditions of head lice (abametapir) and impetigo (ozenoxacin). Although they are both not precisely tropical, they commonly affect the population in tropical and subtropical regions. Impetigo is a contagious skin disease that affects children residing in warm, humid climates.⁹⁸ It is characterized by red sores on the skin, chiefly on open surfaces such as the face, nose, hands, and feet. Besides, ozenoxacin, two other antibiotics are approved for bacterial infections. Thy include delafloxacin, which acts as a DNA gyrase (topoisomerase II) and DNA topoisomerase IV inhibitor, inhibiting the bacterial DNA supercoil relaxation and preventing its replication.^99,100 Another antibiotic is tedizolid phosphate, which is a ribosomal RNA (rRNA) inhibitor and inhibits the peptidyltransferase center (PTC) via binding at the A site interacting with 23S rRNA, leading to structural irregularities, and eventually bacterial protein synthesis.¹⁰¹ Besides bacterial infections, 2 drugs are also approved for the treatment of fungal infections (isavuconazonium and oteseconazole),¹⁰² while one (lenacapavir) is used for the treatment of HIV AIDS.¹⁰³

Besides, five drugs have been approved to affect the haemopoietic system or blood cells directly or indirectly. In this category, avatrombopag is approved to treat thrombocytopenia in liver disease. This drug acts as an agonist for the thrombopoietin receptor (c-Mpl) agonist (TPOR), and thus increases the concentration of platelets via the stimulation of TPOR. This further improves the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells.¹⁰⁴ Also, betrixaban and edoxaban, have been approved as anticoagulants. These drugs inhibit both free and prothrombinase-bound factor Xa, leading to their anticoagulant mechanism.¹⁰⁵ Besides, vorapaxar is approved as an antiplatelet agent and is known to act as an activated receptor (PAR-1) inhibitor, leading to blockage of thrombin-induced platelet aggregation.¹⁰⁶ The last drug in this category is voxelotor, which is used to treat sickle cell disease. It inhibits hemoglobin S (HbS) polymerization, which allows the binding of the α-chain of haemoglobin with the N-terminal valine. This reversibly improves the oxygenated Hb state and prevents HbS polymerization.¹⁰⁷ Besides, the analysis also revealed drugs that were approved for treating glaucoma (omidenepag), gastric ulcers (vonoprazan), kidney disease (finerenone), and actinic keratosis (tirbanibulin).

The chemical structures of the reported drugs other than anticancer drugs are illustrated in Fig. 7(A and B).

Fig. 7 (A and B) Chemical structures of the reported drugs other than anticancer drugs bearing a pyridine ring.

3.3. Analysis of the approved contrast agents bearing a pyridine ring

The contrast agents, commonly termed contrast media, are primarily used to enrich and enhance the radiodensity of organs of interest.¹⁰⁸ This is primarily done to alter the interaction of electromagnetic radiation with the tissue to get a better output image, which can subsequently be thoroughly analyzed to determine the presence or absence of diseases or degree of injury.¹⁰⁹ Due to the use of contrast agents in diagnosis and mainly as they are administered within the body, regulatory agencies, including the US FDA, are particularly interested in their effects in the body. The primary objective is to foresee that they do not cause any deleterious effects in the body and are safely and wholly excreted within a fixed duration.¹¹⁰ The present analysis revealed that three contrast agents are approved bearing a pyridine ring (Table 4), including flortaucipir-F18, which contains the radioactive fluorine isotope. This drug is employed in positron emission tomography (PET) to image the brain of patients to diagnose the presence of Alzheimer's disease (AD).¹¹¹ It drug efficiently crosses the BBB and binds specifically with the tau protein in the aggregated form commonly in AD. However, this drug is also associated with side effects, which include pain at the site of injection, headache and elevated blood pressure.¹¹² The approved radioactive F-18 containing contrast agent is piflufolastat F-18. This drug consists of a prostate-specific membrane antigen (PSMA), which interacts with the prostate-specific antigen overexpressed in the case of prostate cancer. The radioactive F-18 assists in the PET imaging of prostate cancer.¹¹³ The last drug approved is gadopiclenol, which is a gadolinium-based contrast agent possessing paramagnetic properties.¹¹⁴ In magnetic resonance imaging (MRI), upon magnetic field influence, this paramagnetic agent produces a significant magnetic moment, thus enhancing the relaxation rate of protons in its vicinity. This alteration in the dynamics of proton relaxation allows the enhancement of the MRI signal intensity in the tissue system and makes it easily detectable and diagnosed. This drug is used to visualise and detect lesions and abnormal vascularity. The chemical structures of the approved contrast agents are presented in Fig. 8.

Table 4 Approved contrast agents bearing a pyridine ring

S no.	Drug name (brand name) (approval year)	Indication	Biological target	Mechanism	Dosage type and route	Half-life (in h) and excretion	Phase 1 metabolism	DB ID
1	Flortaucipir-F18 2020	PET Alzheimer's disease (AD)	Tau-protein	In the brain, it binds to aggregated tau-protein with low off-target binding to MAO-A and MAO-B to indicate hallmarks of AD	Injection; IV route	17 h; predominantly excreted via urine	Liver metabolism to 4 uncharacterized metabolites	DB14914
2	Piflufolastat F-18 (Pylarify) 2021	PET contrast agent for prostate cancer	Prostate-specific membrane antigen (PSMA) binder	Radiopharmaceutical specifically binds to the PSMA and helps in the visualization of cancerous tissues in the prostate via PET imaging	Injection; IV route	3.47 h; primarily excreted via urine	Not available	DB14805
3	Gadopiclenol (Elucirem) 2022	Contrast agent	Visualization and detection of lesions and abnormal vascularity	This macrocyclic non-ionic complex of gadolinium and a paramagnetic molecule changes the relaxation time of nearby water molecules, where it accumulates and increase contrast	Injection; IV route	1.5 h; 98% excreted via urine	Not metabolized	DB17084

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Fig. 8 Chemical structures of approved contrast agents bearing a pyridine ring.

4. Analysis and conclusion

The present compilation led us to deduce that a total of 54 pyridine-containing drugs was approved during the period of analysis, i.e., 2014–2023 (Fig. 9). The significant drug approval year was 2020, when a total of 10 drugs was approved. This was followed by 2017–18, where 8 drugs were approval each year. Besides this, no drugs containing a pyridine ring system were found to be approved in 2016.

Fig. 9 Statistical analysis of the drugs approved annually.

A significant number of the approved drugs was in the anticancer (18) category, followed by the drugs affecting the CNS (11) system (Fig. 10A). This was followed (other categories; Fig. 10B) by 6 drugs approved to treat the rare conditions, and 5 drugs were found to affect the hemopoietic system. The rare diseases against which drugs are approved include Lambert–Eaton myasthenic syndrome (LEMS), cystic fibrosis, chronic immune thrombocytopenia, Hutchinson–Gilford progeria syndrome, and activated PI3K delta syndrome (APDS). Additionally, 3 agents were approved as contrast agents.

Fig. 10 (A) Share of approved pyridine-containing drugs. (B) Sunburst chart showing approval in other than anticancer category. The other category includes drugs intended for treating CNS disorders, rare conditions, tropical/subtropical diseases, kidney disease, glaucoma, actinic keratosis; antivirals; antibiotics; antiulcer drugs; and antifungal drugs affecting the hematopoietic system.

Next, considering the major drug targets (Fig. 11) explored, we found that 13 drugs out of 18 anticancer drugs were found to inhibit kinases or signalling pathways directly. The important kinases that were affected belong to the class of tyrosine kinases (8 drugs), with two tyrosine kinases explored in other categories of drugs. This was followed by the serine–threonine kinases, particularly the cyclin-dependent kinase (CDK) 4/6, with four anticancer drugs. This was followed by one approval under lipid kinase, specifically PI3K (alpelisib). Besides, one drug, sonidegib, was found to interfere with the Hedgehog signalling pathway. Besides, these two drugs were approved as dehydrogenase inhibitors. In the other categories, CGRP was the major receptor explored, followed by factor Xa, DNA gyrase, NK-1, etc.

Fig. 11 Major drug targets explored during the period of analysis.

Next, we considered the major phase 1 enzymes carrying out the metabolism, and the analysis revealed that most of the compounds were metabolized by the multiple involvement of metabolizing enzymes (26). The major metabolizing enzyme was CYP3A4 (12), followed by CYP3A (2), and 1 drug metabolized each by CYP1A2, N-acetyltransferase 2 hepatic carboxylesterase-1, and carboxylesterase 1A1. Additionally, oteseconazole was found to have a maximum half-life duration of 138 days, while omidenepag was found to have the shortest half-life of 30 min. Next, we analyzed the formulation types for the approved drug candidates. The analysis revealed (Fig. 12A) that 50% of the total drugs approved were in the form of tablets, followed by 17% capsules and 15% injection routes (i.v or i.m). As expected, the route of administration analysis revealed (Fig. 12A) that 74% of drugs were given or administered through the oral route, followed by 15% via the i.v or i.m route, 6% of drugs both via oral and injection, and 5% drugs had topical use.

Fig. 12 Approved drugs (A) dosage forms and (B) route of administration.

Next, considering the important functional group analysis (Fig. 13A) of the approved drugs, we found that 10 sulfur group-containing drugs were approved. This was followed by a tie between the hydroxy (–OH) and amine (–NH₂) groups, with 8 drugs approved in each case. This was followed by 6 drugs approved possessing a carboxylic acid (–COOH) group, which was further followed by the approval of 4 drugs bearing the sulphonamide group, and 3 drugs were found to carry a phosphorus or phosphate group as the functional entity. Besides, two drugs were found to carry both –OH and –COOH functionality. The analysis also revealed that none of the approved drugs were found to contain nitro (–NO₂) as a functional group.

Fig. 13 Analysis revealing (A) major functional groups that were found to be substituted in the approved drug, along with (B) halogens, as revealed in the pie chart. (C) Share of pyridine drugs, which were found to be fused or substituted with other heterocycles or aromatics.

Next, we move to the halogen family, which is reported to modulate steric and lipophilic aspects in drug–target complexes.¹¹⁵ Additionally, halogen bonds are identified as a key interaction in ligand–target complexes, an intermolecular interaction that provides stability to the complexes and enhances the affinity for the target.¹¹⁶ Various interactions formed by halogens at the target site have proven that halogens are a key aspect in rational drug design.¹¹⁷ The analysis revealed (Fig. 13B) that the presence of fluorine was noted in 32 compounds, followed by 11 compounds containing a chloro (–Cl) group and 2 drugs containing bromine as a functional entity. None of the compounds approved were found to possess an iodine (–I) group as a functional entity. Usually, in drug discovery, most pharmacophores are clubbed together via the hybrid drug design strategy to maximize their biological receptor interaction and improve physiochemical outcomes. In the present analysis (Fig. 13C), we identified pyridine-containing drugs, but other heterocycles were also present. The analysis revealed that pyridine was in fused form in 16 drugs with other aromatics/heterocyclics ring. Besides fusion, the pyrrolidine/pyrrole hybridisation attachment was seen in almost 10 approved drugs. This was followed by the presence of pyrimidine (9), piperazine (8), pyrazole/pyrazoline (7), imidazole (6), and thiazole (4). Besides, all the approved drugs in the analysis were aromatic.

As stated in the reactivity of pyridine, the primary reactivity site is in position 2. Similar to the reactivity pattern, 90% of the approved drugs were found to be substituted at position 2. Besides, 55% of the drugs consist of di-substitution primarily at 2,5-positions. Also, more than 50% of the total pyridine-approved drugs were found to be devoid of any stereocentre and were achiral.

5. Future perspective and scope of pyridine

The heterocyclic ring, pyridine, is a key structural motif in numerous natural molecules such as vitamins (niacins and vitamin B6), alkaloids (trigonelline), coenzymes (nicotinamide adenine dinucleotide), etc. Similarly, pyridine also plays a major role as a structural motif in numerous drugs such as antioxidants, antivirals, anti-bacterial, and anti-cancer, and pesticides. The unique chemistry and parameters of pyridine make it a key heterocyclic molecule in drug discovery and medicinal chemistry. One of its key characteristics is that it helps improve the water solubility of molecule via its weak basic character. Also, the small molecular size, higher stability and weak basic character of pyridine further make it an important bioisostere for benzene and other heterocyclic rings. One of these examples is the development of mepyramine (which possess a pyridine ring as bioisostere of imidazole) from cimetidine (it has an imidazole ring). Some of these replacements were discussed above in Scheme 1. Thus, the abovementioned physicochemical features of the pyridine moiety present it as key replacement in structural pharmacophores for better water solubility, stability, hydrogen bond formation at the target site and improved in vivo profile. As a replacement of various amines, amides, benzene and other heterocyclic molecules, pyridine becomes a unique structure in drug discovery. It will help in controlling the activity, efficiency and selectivity of molecules for various subtypes of pharmacological targets. Also, it can provide practical solutions in drug development via this replacement process.

In conclusion, pyridine is one of the most privileged and prevalent azaheterocycles and is a significant pharmacophore in drug design. Despite the great efforts in understanding the mechanistic and target effects, further research is reasonable to understand the role of pyridine in biological effects in depth. The possibility of a broad chemical space constituting pyridine and its analogues will assist medicinal chemists in exploring new structural features in rational drug design with high selectivity or specificity for targets. A glance at the data from the last decade of US FDA-approved molecules also asserts the growing interest from researchers in this heterocyclic moiety. In the next decade, it is expected that an upsurge in the exploration of the diverse structural features of pyridine-based pharmacophores for their potential pharmacological application will be observed.

Data availability

No primary research results, software or code has been included and no new data were generated or analysed as part of this review.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

The authors are thankful to their respective organizations for providing necessary infrastructure for this work.

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