Pharmacokinetic Benefits of 3,4-Dimethoxy Substitution of a Phenyl Ring and Design of Isosteres Yielding Orally Available Cathepsin K Inhibitors

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• 作者：James J. Crawford ; Peter W. Kenny ; Jonathan Bowyer ; Calum R. Cook ; Jonathan E. Finlayson ; Christine Heyes ; Adrian J. Highton ; Julian A. Hudson ; Anja Jestel ; Stephan Krapp ; Scott Martin ; Philip A. MacFaul ; Benjamin P. McDermott ; Thomas M. McGuire ; Andrew D. Morley ; Jeffrey J. Morris ; Ken M. Page ; Lyn Rosenbrier Ribeiro ; Helen Sawney ; Stefan Steinbacher ; Caroline Smith ; Alexander G. Dossetter
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：October 25, 2012
• 年：2012
• 卷：55
• 期：20
• 页码：8827-8837
• 全文大小：495K
• 年卷期：v.55,no.20(October 25, 2012)
• ISSN：1520-4804

文摘

Rational structure-based design has yielded highly potent inhibitors of cathepsin K (Cat K) with excellent physical properties, selectivity profiles, and pharmacokinetics. Compounds with a 3,4-(CH₃O)₂Ph motif, such as 31, were found to have excellent metabolic stability and absorption profiles. Through metabolite identification studies, a reactive metabolite risk was identified with this motif. Subsequent structure-based design of isoteres culminated in the discovery of an optimized and balanced inhibitor (indazole, 38).