학술논문
(1R,2R)-N-(1-Cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): APotent and Highly Selective Cathepsin K Inhibitor for the Treatmentof Osteoarthritis.
Document Type
Article
Author
Dossetter, Alexander G.; Beeley, Howard; Bowyer, Jonathan; Cook, Calum R.; Crawford, James J.; Finlayson, Jonathan E.; Heron, Nicola M.; Heyes, Christine; Highton, Adrian J.; Hudson, Julian A.; Jestel, Anja; Kenny, Peter W.; Krapp, Stephan; Martin, Scott; MacFaul, Philip A.; McGuire, Thomas M.; Gutierrez, Pablo Morentin; Morley, Andrew D.; Morris, Jeffrey J.; Page, Ken M.
Source
Subject
*OSTEOARTHRITIS treatment
*INDOLE compounds
*DRUG synergism
*CATHEPSINS
*ENZYME inhibitors
*DRUG use testing
*DRUG stability
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Language
ISSN
0022-2623
Abstract
Directed screening of nitrile compounds revealed 3as a highly potent cathepsin K inhibitor but with cathepsinS activityand very poor stability to microsomes. Synthesis of compounds withreduced molecular complexity, such as 7, revealed keySAR and demonstrated that baseline physical properties and in vitrostability were in fact excellent for this series. The tricycle carbolineP3 unit was discovered by hypothesis-based design using existing structuralinformation. Optimization using small substituents, knowledge frommatched molecular pairs, and control of lipophilicity yielded compoundsvery close to the desired profile, of which 34(AZD4996)was selected on the basis of pharmacokinetic profile. [ABSTRACT FROM AUTHOR]