RESUMEN
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.
RESUMEN
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.
Asunto(s)
Química Farmacéutica/métodos , Pirimidinas/química , Renina/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Pirimidinas/síntesis química , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
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.