title: Triazolinones as nonpeptide angiotensin II antagonists. 1. Synthesis and evaluation of potent 2,4,5-trisubstituted triazolinones.
abstract: A series of 2,4-dihydro-2,4,5-trisubstituted-3H-1,2,4-triazol-3-ones was prepared via several synthetic routes and evaluated as AII receptor antagonists in vitro and in vivo. The preferred compounds contained a [2'-(5-tetrazolyl)biphenyl-4-yl]methyl side chain at N4 and an n-butyl group at C5. A number of these bearing an alkyl or aralkyl substituent at N2 showed in vitro potency in the nanomolar range (rabbit aorta membrane receptor), and several of these, e.g., the 2,2-dimethyl-1-propyl analogue (54, IC50 = 2.1 nM), effectively blocked the AII pressor response in conscious rats with significant duration (2.5 h at 1 mg/kg orally for 54). Among analogues possessing aryl substituents at N2, ortho substitution on the phenyl moiety resulted in several derivatives with in vitro potency in the low nanomolar range. One of these, featuring a 2-(trifluoromethyl)phenyl substituent at N2 (25, IC50 = 1.2 nM), was effective at 1 mg/kg orally in the rat model, with a duration of > 6 h. Implications for hydrophobic and hydrogen-bonding interactions with the AT1 receptor are discussed.
authors.affiliation: Merck Research Laboratories, Rahway, New Jersey 07065.
authors.forename: L L
authors.initials: LL
authors.lastname: Chang
authors.forename: W T
authors.initials: WT
authors.lastname: Ashton
authors.forename: K L
authors.initials: KL
authors.lastname: Flanagan
authors.forename: R A
authors.initials: RA
authors.lastname: Strelitz
authors.forename: M
authors.initials: M
authors.lastname: MacCoss
authors.forename: W J
authors.initials: WJ
authors.lastname: Greenlee
authors.forename: R S
authors.initials: RS
authors.lastname: Chang
authors.forename: V J
authors.initials: VJ
authors.lastname: Lotti
authors.forename: K A
authors.initials: KA
authors.lastname: Faust
authors.forename: T B
authors.initials: TB
authors.lastname: Chen
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D001665:Binding Sites; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D014230:Triazoles; D000804:Angiotensin II