Pharmacology and pharmacokinetics of a novel nonpeptide angiotensin II receptor antagonist--DMP 811.
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.
Wong
P C
PC
Cardiovascular Diseases Research, DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0400, USA.
Huang
S M
SM
Ardecky
R J
RJ
Carini
D J
DJ
Chiu
A T
AT
Price
W A
WA
Agra
A M
AM
Wexler
R R
RR
Timmermans
P B
PB
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
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013777:Tetrazoles; C085640:DMP 811