(1R,2R)-N-(1-Cyanocyclopropyl)-2-(6-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (AZD4996): A Potent and Highly Selective Cathepsin K Inh

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• 作者：Alexander G. Dossetter ; Howard Beeley ; Jonathan Bowyer ; Calum R. Cook ; James J. Crawford ; Jonathan E. Finlayson ; Nicola M. Heron ; Christine Heyes ; Adrian J. Highton ; Julian A. Hudson ; Anja Jestel ; Peter W. Kenny ; Stephan Krapp ; Scott Martin ; Philip A. MacFaul ; Thomas M. McGuire ; Pablo Morentin Gutierrez ; Andrew D. Morley ; Jeffrey J. Morris ; Ken M. Page ; Lyn Rosenbrier Ribeiro ; Helen Sawney ; Stefan Steinbacher ; Caroline Smith ; Madeleine Vickers
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 26, 2012
• 年：2012
• 卷：55
• 期：14
• 页码：6363-6374
• 全文大小：520K
• 年卷期：v.55,no.14(July 26, 2012)
• ISSN：1520-4804

文摘

Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.