RESUMO
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.
Assuntos
Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Piridinas/síntese química , Pirimidinas/síntese química , Quinazolinonas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Masculino , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Quinazolinonas/farmacocinética , Quinazolinonas/farmacologia , Coelhos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Matrix metalloproteinase-13 (MMP13) is a Zn(2+)-dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structure-based drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients.
Assuntos
Cartilagem/metabolismo , Artropatias/metabolismo , Metaloproteinase 13 da Matriz/fisiologia , Animais , Colágeno/química , Colágeno/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/farmacologia , Humanos , Íons , Metaloproteinase 13 da Matriz/química , Metaloproteinase 13 da Matriz/metabolismo , Modelos Biológicos , Modelos Químicos , Modelos Moleculares , Coelhos , Ratos , Zinco/químicaRESUMO
Osteoarthritis (OA) is a degenerative disease characterized by an irreversible loss of articular cartilage. Although surgically induced animal OA models are commonly used in drug efficacy assessment, degradation of type II collagen, an important component of articular cartilage is not routinely evaluated. Here, the medial meniscectomy surgical model (MMT) in Lewis rats was evaluated for proteoglycan loss with toluidine blue staining and collagen degradation with immunohistochemical staining for a collagen cleavage C-neoepitope, using a novel anti-type II collagen neoepitope antigen (TIINE) antibody. Femorotibial joints were collected for histology at 0 (no surgery), 3, 7, 14, 21, 28, 35, and 42 days postsurgery. Following MMT surgery, the medial tibial articular cartilage had proteoglycan matrix loss by day 3 that reached subchondral bone by days 28-42. Femoral cartilage damage occurred by day 14. TIINE staining was present at basal levels in growth plates and articular cartilage of all joints while all MMT-treated animals had increased intensity and area of staining in erosions that colocalized with proteoglycan loss. The MMT model produces a progressive pattern of cartilage damage resembling human OA lesions, making it useful, when evaluated with cartilage biomarkers, for assessing changes in cartilage degradation.