Synthesis, binding studies, and in vivo biological evaluation of novel non-peptide antihypertensive analogues

摘要

AT_1 antagonists (SARTANs) constitute the last generation of drugs for the treatment of hypertension, designed and synthesized to mimic the C-terminal segment of the vasoconstrictive hormone angiotensin Ⅱ (AngⅡ). They exert their action by blocking the binding of AngⅡ on the AT_1 receptor. Up to date eight AT_1 antagonists have been approved for the regulation of high blood pressure. Although these molecules share common structural features and are designed to act under the same mechanism, they have differences in their pharmacological profiles and antihypertensive efficacy. Thus, there is still a need for novel analogues with better pharmacological and financial profiles. An example of a novel synthetic non-peptide AT_1 antagonist which devoids the classical template of SARTANs is MM1. In vivo studies showed that MMK molecules, which fall in the same class of MM1, had a significant antihypertensive (40-80% compared to the drug losartan) activity. However, in vitro affinity studies showed that losartan has considerably higher affinity. The theoretical docking studies showed that MM1 acts on the same site of the receptor as losartan. They exert hydrophobic interactions with amino acid Val108 of the third helix of the AT_1 receptor and other hydrophobic amino acids in spatial vicinity. In addition, losartan favors multiple hydrogen bondings between its tetrazole group with Lys199. These additional interactions may in part explain its higher in vitro binding affinity.