1403499-41-1Relevant articles and documents
Pharmacokinetic benefits of 3,4-dimethoxy substitution of a phenyl ring and design of isosteres yielding orally available cathepsin K inhibitors
Crawford, James J.,Kenny, Peter W.,Bowyer, Jonathan,Cook, Calum R.,Finlayson, Jonathan E.,Heyes, Christine,Highton, Adrian J.,Hudson, Julian A.,Martin, Scott,MacFaul, Philip A.,McDermott, Benjamin P.,McGuire, Thomas M.,Morley, Andrew D.,Morris, Jeffrey J.,Page, Ken M.,Ribeiro, Lyn Rosenbrier,Sawney, Helen,Smith, Caroline,Dossetter, Alexander G.,Jestel, Anja,Krapp, Stephan,Steinbacher, Stefan
supporting information, p. 8827 - 8837,11 (2020/09/16)
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).
