RESUMO
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.
Assuntos
Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Ácidos Picolínicos/química , Inibidores de Proteases/química , Tetrazóis/química , Administração Oral , Animais , Sítios de Ligação , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Modelos Animais de Doenças , Descoberta de Drogas , Metaloproteinase 13 da Matriz/metabolismo , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Ratos , Tetrazóis/síntese química , Tetrazóis/farmacologia , Zinco/químicaRESUMO
Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific matrix metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, we obtained two chemotypes, 8 and 9, using computer-aided drug design (CADD) and methodical structure-activity relationship (SAR) studies. They occupy the unique S 1'-specificity pocket and do not bind to the Zn(2+) ion. Some pyrido[3,4-d]pyrimidin-4-ones, such as 10a, possess favorable absorption, distribution, metabolism, and elimination (ADME) and safety profiles. 10a effectively prevents cartilage damage in rabbit animal models of osteoarthritis without inducing musculoskeletal side effects when given at extremely high doses to rats.
