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 the discovery of an optimized and balanced inhibitor (indazole, 38).
Subject(s)
Cathepsin K/antagonists & inhibitors , Cyclohexanes/chemical synthesis , Indazoles/chemical synthesis , Animals , Blood Proteins/metabolism , Cells, Cultured , Cyclohexanes/pharmacokinetics , Cyclohexanes/pharmacology , Drug Design , Hepatocytes/metabolism , Humans , Indazoles/pharmacokinetics , Indazoles/pharmacology , Male , Models, Molecular , Protein Binding , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In the presence of substoichiometric quantities of potassium tert-butoxide and an additional metal salt, amide-tethered diacids undergo double Michael reactions with alkynones to provide highly functionalized pyroglutamic acid derivatives. The metal salt was found to play an important role in improving the diastereoselectivities of the reactions.
