Design, Synthesis and Biological Evaluation of New Rennin Inhibitors

S.P. Likitha Rao^*1, Anil Middah¹, Neeraj Tandan^2
1Department of Pharmaceutics,OPJS University, Rajasthan, India
²SARC (Scientific and Applied Research Centre) – Meerut

A B S T R A C T
Hypertension is a major risk factor for cardiovascular diseases such as stroke, myocardial infarction, and heart failure, the leading causes of death in the western world. Inhibitors of rennin –angiotensin system (RAS) have proved to successful treatments for hypertension. As rennin specifically catalyses the rate-limiting step of the RAS, it represents the optimal target for RAS inhibition. Several peptide-like rennin inhibitors have been synthesized previously, but poor pharmacokinetic properties meant that these compounds were not clinically useful. We employed a combination of molecular modelling and crystallographic structure analysis to design rennin inhibitors lacking the extended peptide-like backbone of earlier inhibitors. This led to the discovery 169 ET_A receptors have been selected for the study.  24 molecules were carefully selected as the training set without any redundancy in information content in terms of both structural features and activity ranges. Structures of all synthesized compounds have been corroborated on the basis of elemental IR, Proton NMR and mass spectra-analytical data.
Keywords: Rennin inhibitors, antihypertensive activity, blood pressure, molecular modelling, rennin- angiotensin system.