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
The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.
Subject(s)
Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Cathepsin K/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Nitriles/chemistry , Nitriles/pharmacology , Animals , Benzothiazoles/metabolism , Benzothiazoles/pharmacokinetics , Cathepsin K/metabolism , Dogs , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Microsomes, Liver/metabolism , Models, Molecular , Nitriles/metabolism , Nitriles/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
Directed screening of nitrile compounds revealed 3 as a highly potent cathepsin K inhibitor but with cathepsin S activity and very poor stability to microsomes. Synthesis of compounds with reduced molecular complexity, such as 7, revealed key SAR and demonstrated that baseline physical properties and in vitro stability were in fact excellent for this series. The tricycle carboline P3 unit was discovered by hypothesis-based design using existing structural information. Optimization using small substituents, knowledge from matched molecular pairs, and control of lipophilicity yielded compounds very close to the desired profile, of which 34 (AZD4996) was selected on the basis of pharmacokinetic profile.
