Rational Design and Synthesis of AT1R Antagonists.

Stamatia Vassiliou,Nikitas Georgiou,Andreas G Tzakos,Vasileios K Gkalpinos,Thomas Mavromoustakos,Spyridon D Katsakos

doi:10.3390/molecules26102927

Abstract

Hypertension is one of the most common diseases nowadays and is still the major cause of premature death despite of the continuous discovery of novel therapeutics. The discovery of the Renin Angiotensin System (RAS) unveiled a path to develop efficient drugs to fruitfully combat hypertension. Several compounds that prevent the Angiotensin II hormone from binding and activating the AT1R, named sartans, have been developed. Herein, we report a comprehensive review of the synthetic paths followed for the development of different sartans since the discovery of the first sartan, Losartan.

Highlights

Hypertension is a medical condition where the blood pressure in the arteries is elevated
Angiotensin II (AII) receptor blockers are a class of molecules that act in the Renin Angiotensin System (RAS) through binding to the AT1 receptor (Angiotensin II receptor type 1, AT1R) and preventing its activity
Duncia et al published the discovery of DuP753, a potent, orally active nonpeptide Angiotensin II (AII) receptor antagonist and other derivatives

Summary

Introduction

Hypertension is a medical condition where the blood pressure in the arteries is elevated. Duncia et al published the discovery of DuP753 (losartan), a potent, orally active nonpeptide Angiotensin II (AII) receptor antagonist (see Figure 1) and other derivatives. Their aim was to develop a peptidemimetic molecule based on structural features of the AII peptide, which are responsible for its biological activity. The first hypothesis was that both AII and the lead molecules of the Takeda Pharmaceutical Company Limited (imidazole-5-acetic acid derivatives) [4], bind to the same receptor site They hypothesized that the poor binding affinity of the Takeda’s molecules was due to their small size and partial resemblance to the AII. One common structural characteristic of the commercially AT1R antagonists is that they contain an acidic group such as carboxylate or tetrazole or 5-oxo-1,2,4-oxadiazole

Synthetic Routes of Losartan

Synthetic Routes for Valsartan

Conclusions