Pharmacokinetic Benefits of 3,4-Dimethoxy Substitution of a Phenyl Ring and Design of Isosteres Yielding Orally Available Cathepsin K Inhibitors
详细信息 查看全文
- 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).