ABSTRACT
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.
Subject(s)
Chemistry, Pharmaceutical/methods , Pyrimidines/chemistry , Renin/antagonists & inhibitors , Animals , Crystallography, X-Ray , Drug Design , Inhibitory Concentration 50 , Models, Chemical , Models, Molecular , Molecular Conformation , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Renin/antagonists & inhibitors , Crystallography, X-Ray , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/drug effects , Enzyme Inhibitors/chemical synthesis , Humans , Models, Molecular , Molecular Structure , Piperazines/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
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.
