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 AT(1) in rat adrenal tissues with an 1C(50) of 6 nM, but not for the subtype receptor AT(2). In the isolated rabbit aorta, DMP 811 inhibited the contractile response to angiotensin II selectively and noncompetitively with a Kg value of 0.1 nM. In conscious renal hyperte nsive rats, DMP 811 decreased blood pressure with i.v. and p.o. ED(30s ) of 0.005 and 0.03 mg/kg, respectively (p.o. ED(30) 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 bioava ilabilities of 7 and 29% in rats and dogs, respectively, after a solut ion dose and 8 and 13%, respectively, after a suspension or capsule do sing. Our study indicates that DMP 811 is a selective and insurmountab le AT(1) receptor antagonist and is a 20-fold more potent orally-activ e antihypertensive agent than losartan.