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

The discovery, in vitro and in vivo studies of the highly potent AT1 antagonist 12a (BR-A-657, Fimasartan) 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 0.13 nM, respectively] and inhibited strongly in vivo AngII-induced pressor response in pithed rats with an ED₅₀ of 0.018 mg/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.