RESUMEN
Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.
Asunto(s)
Metaloproteinasa 13 de la Matriz/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz/síntesis química , Inhibidores de la Metaloproteinasa de la Matriz/farmacología , Osteoartritis/tratamiento farmacológico , Pirimidinas/síntesis química , Pirimidinas/farmacología , Tetrazoles/síntesis química , Tetrazoles/farmacología , Animales , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Colagenasas/efectos de los fármacos , Perros , Diseño de Fármacos , Humanos , Riñón/metabolismo , Macaca fascicularis , Masculino , Inhibidores de la Metaloproteinasa de la Matriz/toxicidad , Modelos Moleculares , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A series of phenyl piperidine alpha-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13, are dual-sparing of MMP-1 and MMP-14 (MT1-MMP) and exhibit oral bioavailability in rats.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Administración Oral , Animales , Disponibilidad Biológica , Ácidos Hidroxámicos/administración & dosificación , Metaloproteinasa 1 de la Matriz/efectos de los fármacos , Metaloproteinasa 14 de la Matriz/efectos de los fármacos , Piperidinas , Ratas , Bibliotecas de Moléculas Pequeñas , Solubilidad , Especificidad por Sustrato , SulfonasRESUMEN
Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.
Asunto(s)
Inhibidores de la Metaloproteinasa de la Matriz , Osteoartritis/tratamiento farmacológico , Ácidos Picolínicos/química , Inhibidores de Proteasas/química , Tetrazoles/química , Administración Oral , Animales , Sitios de Unión , Cartílago/efectos de los fármacos , Cartílago/metabolismo , Dominio Catalítico , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Metaloproteinasa 13 de la Matriz/metabolismo , Ácidos Picolínicos/síntesis química , Ácidos Picolínicos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Ratas , Tetrazoles/síntesis química , Tetrazoles/farmacología , Zinc/químicaRESUMEN
Aggrecanase-2 (a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5)), a member of the ADAMTS protein family, is critically involved in arthritic diseases because of its direct role in cleaving the cartilage component aggrecan. The catalytic domain of aggrecanase-2 has been refolded, purified, and crystallized, and its three-dimensional structure determined to 1.4A resolution in the presence of an inhibitor. A high resolution structure of an ADAMTS/aggrecanase protein provides an opportunity for the development of therapeutics to treat osteoarthritis.