title: Synthesis and antihypertensive activity of pyrimidin-4(3H)-one derivatives as losartan analogue for new angiotensin II receptor type 1 (AT1) antagonists.
abstract: The discovery, in vitro and in vivo studies of the highly potent AT(1) 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 AT(1) receptor antagonists. Among them, 12a containing thioamido moiety displayed both high in vitro functional antagonism and binding affinity [IC(50)=0.42 and 0.13 nM, respectively] and inhibited strongly in vivo AngII-induced pressor response in pithed rats with an ED(50) 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 AT(1) selective antagonist having stronger in vivo potency than losartan.
authors.affiliation: Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.forename: Byoung Wook
authors.initials: BW
authors.lastname: Yoo
authors.forename: Joon Kwang
authors.initials: JK
authors.lastname: Lee
authors.forename: Ji Han
authors.initials: JH
authors.lastname: Kim
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.forename: Yong Ha
authors.initials: YH
authors.lastname: Chi
authors.forename: Jae Yeol
authors.initials: JY
authors.lastname: Lee
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019808:Losartan / Q000737:chemistry*; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D011744:Pyrimidinones; D019808:Losartan