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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.

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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