RESUMO
Novel 2,4-diaminopyrimidine-based small molecule renin inhibitors are disclosed. Through high throughput screening, parallel synthesis, X-ray crystallography, and structure based drug design, we have developed the first non-chiral, non-peptidic, small molecular template to possess moderate potency against renin. The designed compounds consist of a novel 6-ethyl-5-(1,2,3,4-tetrahydroquinolin-7-yl)pyrimidine-2,4-diamine ring system that exhibit moderate potency (IC(50): 91-650 nM) against renin while remaining 'Rule-of-five' compliant.
Assuntos
Química Farmacêutica/métodos , Pirimidinas/química , Renina/antagonistas & inibidores , Animais , Cristalografia por Raios X , Desenho de Fármacos , Concentração Inibidora 50 , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Pirimidinas/síntese química , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Renina/antagonistas & inibidores , Cristalografia por Raios X , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Humanos , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Four lithium atoms in a square-planar arrangement are capped by two carbon atoms and encapsulated by NSiMe3 chelation in the dilithium methanide salt 1. This air- and moisture-sensitive complex is formed by the reaction of CH2 (Ph2 P=NSiMe3 )2 with alkyl- or aryllithium reagents.