RESUMO
SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1' pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.
Assuntos
Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Quelantes/química , Quelantes/farmacologia , Relação Estrutura-Atividade , Zinco/químicaRESUMO
Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1' pocket.
Assuntos
Quelantes/farmacologia , Metaloproteinase 13 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/farmacologia , Domínio Catalítico , Quelantes/química , Metaloproteinase 13 da Matriz/química , Modelos Moleculares , Inibidores de Proteases/química , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Chemistry has been developed to specifically functionalize two structurally similar classes of indole-based MK2 inhibitors at positions prompted by a combination of X-ray crystallographic and computer assisted drug design. A gain in molecular potency was obtained by introducing aminomethyl groups to the lactam rings of 6-arylcarbamoyl-tetrahydro-beta-carbolinone and 6-arylcarbamoyl-dihydropyrazino[1,2-a]indolone MK2 inhibitors. In addition, improvements in molecular potency were achieved by expansion of the lactam from a 6- to 7-membered ring leading to 7-arylcarbamoyl-tetrahydro-[1,4]diazepino[1,2-a]indolones.