Discovery and optimisation of 1-acyl-2-benzylpyrrolidines as potent dual orexin receptor antagonists

Jodi T. Williams; John Gatfield; Catherine Roch; Alexander Treiber; Francois Jenck; Martin H. Bolli; Christine Brotschi; Thierry Sifferlen; Bibia Heidmann; Christoph Boss

doi:10.1039/C5MD00074B

Discovery and optimisation of 1-acyl-2-benzylpyrrolidines as potent dual orexin receptor antagonists†

Jodi T. Williams,*^a John Gatfield,^a Catherine Roch,^a Alexander Treiber,^a Francois Jenck,^a Martin H. Bolli,^a Christine Brotschi,^a Thierry Sifferlen,^a Bibia Heidmann^a and Christoph Boss^a

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^a Drug Discovery Chemistry, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123, Switzerland
E-mail: jodi.williams@actelion.com

Abstract

Starting from a thienopiperidine lead compound with high intrinsic clearance in rat and human liver microsomes and low aqueous solubility, a novel series of 1-acyl-2-benzylpyrrolidines were discovered as potent and competitive dual orexin receptor antagonists. Metabolic stability was improved to afford oral exposure, and aqueous solubility was increased by twentyfold, providing compounds suitable for preclinical evaluation. Compound 27 showed insurmountable antagonism at both orexin 1 and orexin 2 receptor subtypes and displayed a comparable sleep-promoting effect in the rat to almorexant and suvorexant.

MedChemComm

Discovery and optimisation of 1-acyl-2-benzylpyrrolidines as potent dual orexin receptor antagonists†

Abstract

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Discovery and optimisation of 1-acyl-2-benzylpyrrolidines as potent dual orexin receptor antagonists

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