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 K_B value of 0.1 nM. In conscious renal hypertensive rats, DMP 811 decreased blood pressure with i.v. and p.o. ED3_30s 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.

Key Words:

• angiotensin II receptor antagonist
• blood pressure
• hypertension
• renin-angiotensin system