title: Pharmacology and pharmacokinetics of a novel nonpeptide angiotensin II receptor antagonist--DMP 811.
abstract: DMP 811 exhibited high binding affinity for the angiotensin II subtype receptor AT1 in rat adrenal tissues with an IC50 of 6 nM, but not for the subtype receptor AT2. In the isolated rabbit aorta, DMP 811 inhibited the contractile response to angiotensin II selectively and noncompetitively with a KB value of 0.1 nM. In conscious renal hypertensive rats, DMP 811 decreased blood pressure with i.v. and p.o. ED30s of 0.005 and 0.03 mg/kg, respectively (p.o. ED30 for losartan = 0.59 mg/kg). In conscious furosemide-treated dogs, DMP 811 given either at 0.3 or 1 mg/kg p.o. decreased blood pressure. DMP 811 has oral bioavailabilities of 7 and 29% in rats and dogs, respectively, after a solution dose and 8 and 13%, respectively, after a suspension or capsule dosing. Our study indicates that DMP 811 is a selective and insurmountable AT1 receptor antagonist and is a 20-fold more potent orally-active antihypertensive agent than losartan.
authors.affiliation: Cardiovascular Diseases Research, DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0400, USA.
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: S M
authors.initials: SM
authors.lastname: Huang
authors.forename: R J
authors.initials: RJ
authors.lastname: Ardecky
authors.forename: D J
authors.initials: DJ
authors.lastname: Carini
authors.forename: A T
authors.initials: AT
authors.lastname: Chiu
authors.forename: W A
authors.initials: WA
authors.lastname: Price
authors.forename: A M
authors.initials: AM
authors.lastname: Agra
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
authors.forename: P B
authors.initials: PB
authors.lastname: Timmermans
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001681:Biological Assay; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D006168:Guinea Pigs; D006978:Hypertension, Renovascular; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013777:Tetrazoles; C085640:DMP 811