Pharmacokinetic benefits of 3, 4-dimethoxy substitution of a phenyl ring and design of isosteres yielding orally available cathepsin K inhibitors

…, PA MacFaul, BP McDermott, TM McGuire…

Index: 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 Journal of Medicinal Chemistry, 2012 , vol. 55, # 20 p. 8827 - 8837,11 Title/Abstract Full Text Show Details Crawford, James J.; Kenny, Peter W.; Bowyer, Jonathan; Cook, Calum R.; Finlayson, Jonathan E.; Heyes, Christine; Highton, Adrian J.; Hudson, Julian A.; Jestel, Anja; Krapp, Stephan; 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; Steinbacher, Stefan; Smith, Caroline; Dossetter, Alexander G. Journal of Medicinal Chemistry, 2012 , vol. 55, # 20 p. 8827 - 8837

Full Text: HTML

Citation Number: 8

Abstract

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 ...