EXP063, a nonpeptide angiotensin II and beta adrenergic receptor antagonist.
EXP063 (4-[[4-[[3-(N-isopropylamino)-2-hydroxypropyl]oxy]- indole-2-carboxamido]methyl]-2-propyl-1-[(2'-(1H-tetrazol-5-yl)bip henyl-4 - yl)methyl]imidazole-5-carboxylic acid) was designed to possess both the angiotensin II (Ang II) and beta adrenergic receptor antagonistic properties. EXP063 inhibited the specific binding of [125I]Sar1,lle8-Ang II in rat adrenal membranes with Ki values of 3.9 +/- 0.6 nM for the Ang II type 1 and > 1 microM for the Ang II type 2 receptor binding sites. It displaced [3H]dihydroalprenolol in the rat cerebral frontal cortex with a Ki of 80 +/- 13 nM. EXP063 antagonized the contractile effect of Ang II competitively (pA2 = 8.9 +/- 0.1) and selectively in rabbit aorta and guinea pig ileum. EXP063 appears to be a partial beta adrenoceptor agonist as it increased heart rate in vitro and in vivo. At 1 and 10 microM, it inhibited the positive inotropic effect of isoproterenol in guinea pig atria. In pithed rats, EXP063 was more potent in blocking the pressor effect of Ang II than the positive chronotropic effect of isoproterenol. In renal hypertensive rats, EXP063 given i.v. produced a long-lasting decrease in blood pressure for at least 6 hr with an ED30 of 0.53 mg/kg. In summary, this study demonstrates that EXP063 is a novel chemical entity possessing both the Ang II and beta adrenergic receptor blocking properties and, thus, represents a promising agent for the treatment of hypertension and congestive heart failure.
Wong
P C
PC
Du Pont Merck Pharmaceutical Company, Wilmington, Delaware.
Duncia
J V
JV
Chiu
A T
AT
Olson
R E
RE
Rominger
D H
DH
Tam
S W
SW
Timmermans
P B
PB
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D005240:Feasibility Studies; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D006977:Hypertension, Renal / Q000188:drug therapy / Q000503:physiopathology; D007082:Ileum / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*
D000319:Adrenergic beta-Antagonists; D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013777:Tetrazoles; C084483:EXP 063