RESUMO
A new MMP12 inhibitor series has been identified containing a thiophene moiety. Different approaches have been considered to replace this potential toxicophore. α-Fluorothiophene derivatives were the most interesting compounds. Their synthesis is presented.
Assuntos
Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/química , Tiofenos/química , Metaloproteinase 12 da Matriz/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/farmacologiaRESUMO
A new class of MMP-12 inhibitors was discovered and optimized using structure-based drug design methods. Modeling studies using a known MMP-12 crystal structure identified a new interaction mode for these new MMP-12 inhibitors. Further optimization resulted in the discovery of a compound displaying nanomolar activity against MMP-12 and which was co-crystallized with MMP-12.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Sítios de Ligação , Quelantes/química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Humanos , Metaloproteinase 12 da Matriz , Metaloendopeptidases/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Zinco/químicaRESUMO
The 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 13 and 14 are representatives of a new class of highly potent non nucleoside type inhibitors of HIV-1 reverse transcriptase. To conduct SAR studies on these two lead compounds, 102 new analogues were prepared. Thirty-three compounds displayed nanomolar range activity in vitro against wild-type HIV-1, and among these, 18 were active against the 103N, Y181C, and Y188L mutant strains with IC50 values inferior to 1 microM. Evaluation of this group of analogues against an additional eight single [100I, 101E, 106A, 138K, 179E, 190A, 190S, 227C] and four double HIV mutant strains [100I + 103N, 101E + 103N, 103N + 181C, and 227L + 106A], which are often present in HIV infected patients, permitted the selection of eight compounds, 17x, 18b, 18c, 18f, 18g, 27, 30, and 42, which are globally more active than the lead molecules 13/14, emivirine and the currently used NNRTI, nevirapine. Further comparison of the 3'-CN-substituted benzoylpyridinone compound 18c, and the corresponding 3'-acrylonitrile-substituted analogue 30, to efavirenz, the reference molecule in anti-HIV therapy today, revealed that the pyridinone analogues displayed a superior inhibition profile in the in vitro cellular assay system. These results form a solid basis for continued optimization of the pyridinone series.