ABSTRACT
The synthesis and biological profile of a novel series of potent and selective inhibitors of cysteine protease cathepsin K (Cat K) are described. Pharmacokinetic evaluation of 12 indicated that some members of this series could be suitable candidates to develop new orally active therapeutic agents for the treatment of osteoporosis.
Subject(s)
Cathepsins/antagonists & inhibitors , Nitriles/chemistry , Osteoporosis/drug therapy , Area Under Curve , Cathepsin B/chemistry , Cathepsin K , Cathepsin L , Cathepsins/chemistry , Chemistry, Pharmaceutical , Cysteine Endopeptidases/chemistry , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Models, Chemical , Models, MolecularABSTRACT
We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.
Subject(s)
Benzamides/chemical synthesis , Bone Density Conservation Agents/chemical synthesis , Cathepsins/antagonists & inhibitors , Nitriles/chemical synthesis , Thiazoles/chemical synthesis , Administration, Oral , Animals , Benzamides/chemistry , Benzamides/pharmacology , Biological Availability , Biomarkers/urine , Bone Density Conservation Agents/chemistry , Bone Density Conservation Agents/pharmacology , Bone Resorption/urine , Cathepsin K , Cathepsins/chemistry , Cattle , Collagen/antagonists & inhibitors , Collagen/metabolism , Crystallography, X-Ray , Drug Design , Humans , Kinetics , Macaca mulatta , Models, Molecular , Molecular Structure , Nitriles/chemistry , Nitriles/pharmacology , Rabbits , Rats , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacologyABSTRACT
The chemical synthesis of a series of new penam sulfone derivatives bearing a 2beta-substituted-oxyimino and -hydrazone substituents, their beta-lactamase inhibitory properties against selected enzymes representing class A and C beta-lactamases are reported. The oxime containing penam sulfones strongly inhibited the Escherichia coli TEM-1 and Klebsiella pneumoniae cefotaximase (CTX-1) enzymes, but moderately inhibited the Pseudomonas aeruginosa 46012 cephalosporinase; while the 2beta-substituted-hydrazone derivatives were generally less active against these enzymes. Furthermore, most of the inhibitors enhanced the antibacterial activities of piperacillin (PIP) and ceftazidime (CAZ) particularly against TEM-1 and CTX-1 producing bacterial strains.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Sulfones/chemical synthesis , Sulfones/pharmacology , beta-Lactamase Inhibitors , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Escherichia coli/enzymology , Klebsiella pneumoniae/enzymology , Microbial Sensitivity Tests , Molecular Conformation , Pseudomonas aeruginosa/enzymology , Structure-Activity Relationship , Sulfones/chemistry , beta-Lactamases/chemistryABSTRACT
The synthesis of a series of highly potent and selective inhibitors of cathepsin K based on the 3,4-disubstituted azetidin-2-one warhead is reported. A high degree of potency and selectivity was achieved by introducing a basic nitrogen into the distal part of the P3 element of the molecule. Data from kinetic and mass spectrometry experiments are consistent with the interpretation that compounds of this series transiently acylate the sulfhydrile of cathepsin K.
Subject(s)
Azetidines/pharmacology , Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Azetidines/chemical synthesis , Azetidines/chemistry , Cathepsin K , Cathepsins/chemistry , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Drug Evaluation, Preclinical , Kinetics , Molecular Structure , Structure-Activity RelationshipABSTRACT
A novel series of 3,4-disubstituted azetidinones based inhibitors of the cysteine protease cathepsin K (Cat K) has been identified. Although not optimized, some of these compounds show at least 100-fold selectivity against other cathepsins. The use of cyclic moieties as P2 elements has proven to be crucial to achieve a high degree of selectivity.
