Affordable Access

Publisher Website

Synthesis and antihypertensive activity of pyrimidin-4(3H)-one derivatives as losartan analogue for new angiotensin II receptor type 1 (AT1) antagonists

Authors
Journal
Bioorganic & Medicinal Chemistry Letters
0960-894X
Publisher
Elsevier
Publication Date
Volume
22
Issue
4
Identifiers
DOI: 10.1016/j.bmcl.2011.12.116
Keywords
  • Losartan Analogue
  • Pyrimidin-4(3H)-One
  • Angiotensin Ii Receptor Antagonist
  • Antihypertensive Activity
  • Fimasartan (Br-A-657)
Disciplines
  • Pharmacology

Abstract

Abstract The discovery, in vitro and in vivo studies of the highly potent AT1 antagonist 12a (BR-A-657, Fimasartan) antagonists are presented. A series of pyrimidin-4(3H)-one derivatives as losartan analogue were synthesized and evaluated for a novel class of AT1 receptor antagonists. Among them, 12a containing thioamido moiety displayed both high in vitro functional antagonism and binding affinity [IC50=0.42 and 0.13nM, respectively] and inhibited strongly in vivo AngII-induced pressor response in pithed rats with an ED50 of 0.018mg/kg. Moreover, in vivo evaluation in furosemide-treated rat and conscious renal hypertensive rat models and the pharmacokinetic study showed that 12a is a highly potent and orally active AT1 selective antagonist having stronger in vivo potency than losartan.

There are no comments yet on this publication. Be the first to share your thoughts.