ABSTRACT
Starting from previously disclosed equally potent cathepsin K and S inhibitor 4-propyl-6-(3-trifluoromethylphenyl)pyrimidine-2-carbonitrile 1, a novel 2-phenyl-9H-purine-6-carbonitrile scaffold was identified to provide potent and selective cathepsin S inhibitors.
Subject(s)
Cathepsins/antagonists & inhibitors , Nitriles/chemistry , Protease Inhibitors/chemistry , Purines/chemistry , Catalytic Domain , Cathepsin K/antagonists & inhibitors , Cathepsin K/metabolism , Cathepsins/metabolism , Cell Line , Computer Simulation , Humans , Nitriles/chemical synthesis , Nitriles/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Purines/chemical synthesis , Purines/pharmacology , Pyrimidines/chemistryABSTRACT
Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC(50)=4nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.
Subject(s)
Cathepsin K/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Pyrimidines/chemistry , Administration, Oral , Animals , Binding Sites , Cathepsin K/metabolism , Cell Line , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/pharmacokinetics , Drug Design , High-Throughput Screening Assays , Humans , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.