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Issue 6, 2015
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Discovery and optimisation of 1-acyl-2-benzylpyrrolidines as potent dual orexin receptor antagonists

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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.

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

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The article was received on 20 Feb 2015, accepted on 14 Apr 2015 and first published on 21 Apr 2015


Article type: Concise Article
DOI: 10.1039/C5MD00074B
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Med. Chem. Commun., 2015,6, 1054-1064

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

    J. T. Williams, J. Gatfield, C. Roch, A. Treiber, F. Jenck, M. H. Bolli, C. Brotschi, T. Sifferlen, B. Heidmann and C. Boss, Med. Chem. Commun., 2015, 6, 1054
    DOI: 10.1039/C5MD00074B

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