title: Potent and orally active angiotensin II receptor antagonists with equal affinity for human AT1 and AT2 subtypes.
abstract: In order to block the effects induced by the interactions between angiotensin II (AII) and both AT1 and AT2 receptors, we have pursued the discovery of orally active non-peptide AII antagonists that exhibit potent and equal affinity for human AT1 and AT2 receptor subtypes. A series of previously prepared nanomolar (IC50) trisubstituted 1,2,4-triazolinone biphenyl-sulfonamide dual-acting AII antagonists has been modified at five different positions in order to increase AT2 binding affinity, maintain AT1 activity, and reduce the human adrenal AT2/AT1 potency ratio (IC50 ratio) from > or = 10. The targeted human adrenal potency ratio of < or = 1 was achieved with a number of compounds possessing an ethyl group at C5 of the triazolinone and a 3-fluoro substituent at the N4-biarylmethyl moiety. The most favored of these was compound 44 which exhibited subnanomolar potency at both the AT1 (rabbit aorta) and AT2 (rat midbrain) receptors, with a slight preference for the latter, and had a human adrenal AT2/AT1 IC50 ratio of 1. This tert-butyl sulfonylcarbamate with an N2-[2-bromo-5-(valerylamino)phenyl] substituent had excellent iv activity at 1 mg/kg (100% peak inhibition, > or = 4 h duration of action) and is orally active at 3 mg/kg with > 6 h duration of action in a conscious rat model. The present study shows that the NH of the amide on the N2-aryl moiety is not required for subnanomolar binding affinity to either receptor subtype, although a keto functionality at this position is essential for acceptable AT2 binding. Receptor-ligand binding interactions derived from the structure-activity relationships are discussed with respect to both receptor subtypes.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
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: T B
authors.initials: TB
authors.lastname: Chen
authors.forename: S S
authors.initials: SS
authors.lastname: O'Malley
authors.forename: G J
authors.initials: GJ
authors.lastname: Zingaro
authors.forename: S D
authors.initials: SD
authors.lastname: Kivlighn
authors.forename: P K
authors.initials: PK
authors.lastname: Siegl
authors.forename: V J
authors.initials: VJ
authors.lastname: Lotti
authors.forename: R S
authors.initials: RS
authors.lastname: Chang
mesh_terms: D000284:Administration, Oral; D000311:Adrenal Glands / Q000378:metabolism; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D006801:Humans; D008636:Mesencephalon / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D001713:Biphenyl Compounds; C095758:L 163958; D011945:Receptors, Angiotensin; D013449:Sulfonamides; D014230:Triazoles; D000804:Angiotensin II