RESUMO
A new series of nonpeptidic cathepsin K inhibitors that are based on a beta-substituted cyclohexanecarboxamide motif has been developed. Lead optimization yielded compounds with sub-nanomolar potency and exceptional selectivity profiles against cathepsins B, L, and S. Use of fluorine atoms to block metabolism on the cyclohexyl ring led to compounds with excellent pharmacokinetic properties. Considering the well-established role of cathepsin K in osteoclast-mediated bone turnover, compounds such as (-)-34a (hrab Cat K IC(50) 0.28 nM; >800-fold selectivity vs Cat B, L, and S; PK data in dogs: F 55%, t(1/2) = 15 h) exhibit great potential for development as an orally bioavailable therapeutic for treatment of diseases that involve bone loss.
Assuntos
Amidas/síntese química , Aminoacetonitrila/análogos & derivados , Catepsinas/antagonistas & inibidores , Cicloexanos/síntese química , Amidas/química , Amidas/farmacologia , Aminoacetonitrila/síntese química , Aminoacetonitrila/química , Aminoacetonitrila/farmacologia , Animais , Disponibilidade Biológica , Catepsina K , Catepsinas/química , Cristalografia por Raios X , Cicloexanos/química , Cicloexanos/farmacologia , Cães , Meia-Vida , Masculino , Modelos Moleculares , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Benzamidas/síntese química , Conservadores da Densidade Óssea/síntese química , Catepsinas/antagonistas & inibidores , Nitrilas/síntese química , Tiazóis/síntese química , Administração Oral , Animais , Benzamidas/química , Benzamidas/farmacologia , Disponibilidade Biológica , Biomarcadores/urina , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/urina , Catepsina K , Catepsinas/química , Bovinos , Colágeno/antagonistas & inibidores , Colágeno/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Cinética , Macaca mulatta , Modelos Moleculares , Estrutura Molecular , Nitrilas/química , Nitrilas/farmacologia , Coelhos , Ratos , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The non-basic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compounds are 10- to 20-fold more potent than the corresponding amide derivatives. Compound 8 is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.
