title: Synthesis and SAR studies of novel triazolopyrimidine derivatives as potent, orally active angiotensin II receptor antagonists.
abstract: The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These [1,2,4]-triazolo[1,5-c]pyrimidine and 1,2,4-triazolo[4,3-c]pyrimidine derivatives represent a new class of bicyclic antagonists that produced a potent, oral antihypertensive activity in the renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors and were found to be specific for the AT1 receptor subtype. A SAR study has shown the importance of the 8-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl for oral activity and the critical role of alkyl substituents at 5- and 7-positions. No significant differences were found between the [1,5-c] and [4,3-c]series. UP 269-6 (5-methyl-7-n-propyl-8-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl ]- [1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one, derivative 29) was selected as the lead compound. It was shown to be a highly potent antihypertensive derivative (decrease in mean arterial pressure of 39.6 +/- 7.2 mmHg at 1 mg/kg po in renal artery-ligated rat) with a long duration of action which displayed a high affinity for adrenal AII receptors with a marked selectivity for the AT1 receptor subtype (Ki AT1 = 24 nM; Ki AT2 = 79,200 nM). This compound is currently undergoing extensive pharmacological and clinical development.
authors.affiliation: Carpibem, Rueil Malmaison, France.
authors.forename: E
authors.initials: E
authors.lastname: Nicolaï
authors.forename: G
authors.initials: G
authors.lastname: Curé
authors.forename: J
authors.initials: J
authors.lastname: Goyard
authors.forename: M
authors.initials: M
authors.lastname: Kirchner
authors.forename: J M
authors.initials: JM
authors.lastname: Teulon
authors.forename: A
authors.initials: A
authors.lastname: Versigny
authors.forename: M
authors.initials: M
authors.lastname: Cazes
authors.forename: F
authors.initials: F
authors.lastname: Caussade
authors.forename: A
authors.initials: A
authors.lastname: Virone-Oddos
authors.forename: A
authors.initials: A
authors.lastname: Cloarec
mesh_terms: D000284:Administration, Oral; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001393:Azoles / Q000737:chemistry*; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D008958:Models, Molecular; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001393:Azoles; D011743:Pyrimidines; D013777:Tetrazoles; C088791:UP 269-6