Identification and hit-to-lead optimization of a novel class of CB1 antagonists
| Autor: | Jingchun Yang, Robert Swanson, Maria L. Webb, Koc-Kan Ho, Olson John T, Lihong McAleer, Phillip M. Cowley, Jokiel Patrick, Darren Edwards, Michael Ohlmeyer, James R. Baker, Riviello Christopher, Nick Ward, Jeffrey J. Letourneau |
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| Rok vydání: | 2010 |
| Předmět: |
Agonist
Male Benzimidazole Indoles Stereochemistry medicine.drug_class Clinical Biochemistry Pharmaceutical Science Hypothermia Pharmacology Biochemistry Chemical synthesis chemistry.chemical_compound Mice Structure-Activity Relationship Receptor Cannabinoid CB1 In vivo Drug Discovery medicine Animals Humans Obesity Rats Wistar Molecular Biology Indole test Organic Chemistry Antagonist Hit to lead Rats chemistry Solubility Microsomes Liver Molecular Medicine Benzimidazoles Lead compound |
| Zdroj: | Bioorganicmedicinal chemistry letters. 20(18) |
| ISSN: | 1464-3405 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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