Identification and hit-to-lead optimization of a novel class of CB1 antagonists

Letourneau, Jeffrey J and Jokiel, Patrick and Olson, John and Riviello, Christopher M and Ho, Koc-Kan and McAleer, Lihong and Yang, Jingchun and Swanson, Robert N and Baker, James and Cowley, Phillip and Edwards, Darren and Ward, Nick and Ohlmeyer, Michael H J and Webb, Maria L (2010) Identification and hit-to-lead optimization of a novel class of CB1 antagonists. Bioorganic and Medicinal Chemistry Letters, 20 (18). pp. 5449-5453. ISSN 0960-894X

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Abstract

The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.

Author(s):Letourneau, Jeffrey J, Jokiel, Patrick, Olson, John, Riviello, Christopher M, Ho, Koc-Kan, McAleer, Lihong, Yang, Jingchun, Swanson, Robert N, Baker, James, Cowley, Phillip, Edwards, Darren, Ward, Nick, Ohlmeyer, Michael H J and Webb, Maria L
Item type:Article
ID code:49475
Keywords:animals, benzimidazoles, humans, hypothermia, indoles, mice, microsomes, liver, obesity, rats, rats, wistar, receptor, Cannabinoid, CB1, solubility, structure-activity relationships, Other systems of medicine, Chemical technology, Pharmacy and materia medica, Biochemistry, Organic Chemistry, Drug Discovery, Pharmaceutical Science, Molecular Medicine, Molecular Biology, Clinical Biochemistry
Subjects:Medicine > Other systems of medicine
Technology > Chemical technology
Medicine > Pharmacy and materia medica
Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
Depositing user: Pure Administrator
Date deposited:01 Oct 2014 15:15
Last modified:04 Jan 2019 03:19
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URI:https://strathprints.strath.ac.uk/id/eprint/49475
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