新型非肽类血管紧张素II受体拮抗剂——DMP 811的药理学与药代动力学

Pharmacology and pharmacokinetics of a novel nonpeptide angiotensin II receptor antagonist--DMP 811.

作者信息

Wong P C, Huang S M, Ardecky R J, Carini D J, Chiu A T, Price W A, Agra A M, Wexler R R, Timmermans P B

机构信息

Cardiovascular Diseases Research, DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0400, USA.

出版信息

Clin Exp Hypertens. 1995 Nov;17(8):1233-56. doi: 10.3109/10641969509037406.

DOI:10.3109/10641969509037406

PMID:8563699

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.

摘要

DMP 811对大鼠肾上腺组织中的血管紧张素II亚型受体AT1表现出高结合亲和力，IC50为6 nM，但对亚型受体AT2无亲和力。在离体兔主动脉中，DMP 811选择性地、非竞争性地抑制对血管紧张素II的收缩反应，KB值为0.1 nM。在清醒的肾性高血压大鼠中，DMP 811静脉注射和口服给药的ED30分别为0.005和0.03 mg/kg（氯沙坦的口服ED30 = 0.59 mg/kg）。在清醒的经速尿处理的犬中，口服给予0.3或1 mg/kg的DMP 811可降低血压。溶液给药后，DMP 811在大鼠和犬中的口服生物利用度分别为7%和29%，混悬液或胶囊给药后分别为8%和13%。我们的研究表明，DMP 811是一种选择性且不可克服的AT1受体拮抗剂，是一种口服活性比氯沙坦强20倍的抗高血压药物。