RESUMO
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.
Assuntos
Amidas/síntese química , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Cetonas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Sítios de Ligação , Disponibilidade Biológica , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Catepsina K , Catepsinas/química , Inibidores de Cisteína Proteinase/farmacocinética , Inibidores de Cisteína Proteinase/farmacologia , Modelos Animais de Doenças , Hipocalcemia/tratamento farmacológico , Hipocalcemia/metabolismo , Cetonas/farmacocinética , Cetonas/farmacologia , Ratos , Ratos Wistar , Solubilidade , Relação Estrutura-AtividadeRESUMO
Osteoclast-mediated bone matrix resorption has been attributed to cathepsin K, a cysteine protease of the papain family that is abundantly and selectively expressed in osteoclast. Inhibition of cathepsin K could potentially be an effective method to prevent osteoporosis. Structure-activity studies on a series of reversible ketoamides based inhibitors of cathepsin K have led to identification of potent and selective compounds. Crystallographic studies have given insights into the mode of binding of these inhibitors. A series of ketoamides with varying P1 moieties were first synthesized to find an optimum group that would fit into the S1 subsite of the cysteine protease, cathepsin K. With a desired P1 group in place a variety of heterocyclic analogues in the P' region were synthesized to study their steric and electronic effects. In the process of exploring these P' heterocyclic variations, excellent selectivity was gained over other highly homologous cysteine proteases, including cathepsins L, S, and V. The favorable pharmacokinetic properties of some of these cathepsin K inhibitors in rats make them suitable for evaluation in rodent osteoporosis models. A representative cathepsin K inhibitor was shown to attenuate PTH-stimulated hypercalcemia in the TPTX rat model. These inhibitors provide a viable lead series in the discovery of new therapies for the prevention and treatment of osteoporosis
