Nonpeptide angiotensin II receptor antagonists. XI. Pharmacology of EXP3174: an active metabolite of DuP 753, an orally active antihypertensive agent

PC Wong, WA Price , AT Chiu, JV Duncia, DJ Carini, RR Wexler, AL Johnson and PB Timmermans

Medical Products Department, E. I. du Pont de Nemours & Company, Wilmington, Delaware.

This report describes the pharmacology of (2-n-butyl-4-chloro-1- [(2'- (1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid (EXP3174). EXP3174 is a major metabolite generated after the oral dosing of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H- tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole, potassium salt in rats. It displaced [3H]angiotensin II (AII) from its specific binding sites in rat adrenal cortical membranes with an IC50 of 3.7 x 10(-8) M. In the isolated rabbit aorta, EXP3174 caused nonparallel shifts to the right of the AII concentration-contractile response curves and reduced the maximal response by 30 to 40% with an apparent pA2 value of 10.09 and a KB value of 10(-10) M. At 10(-6) M, EXP3174 did not alter the contractile responses to norepinephrine and KCl. In the spinal pithed rat, EXP3174 at 0.03 to 0.3 mg/kg i.v. also inhibited the pressor responses to AII and angiotensin III noncompetitively and did not change the pressor responses to vasopressin and norepinephrine. When given i.v. and cumulatively to normotensive rats at 0.003 to 0.3 mg/kg, EXP3174 did not alter blood pressure but inhibited the pressor response to AII. In conscious renal artery-ligated rats, EXP3174 decreased blood pressure with an i.v. ED30 of 0.038 mg/kg and a p.o. ED30 of 0.66 mg/kg. These results demonstrate that EXP3174 is a selective and noncompetitive AII receptor antagonist and lacks agonistic effect. As EXP3174 is a potent antihypertensive agent, it may be responsible for part of the antihypertensive effect of DuP 753 in rats.

Volume 255, Issue 1, pp. 211-217, 10/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				A. Veerappan, A. C. Reid, R. Estephan, N. O'Connor, M. Thadani-Mulero, M. Salazar-Rodriguez, R. Levi, and R. B. Silver Mast cell renin and a local renin-angiotensin system in the airway: Role in bronchoconstriction PNAS, January 29, 2008; 105(4): 1315 - 1320. [Abstract] [Full Text] [PDF]

				E. Messadi-Laribi, V. Griol-Charhbili, A. Pizard, M.-P. Vincent, D. Heudes, P. Meneton, F. Alhenc-Gelas, and C. Richer Tissue Kallikrein Is Involved in the Cardioprotective Effect of AT1-Receptor Blockade in Acute Myocardial Ischemia J. Pharmacol. Exp. Ther., October 1, 2007; 323(1): 210 - 216. [Abstract] [Full Text] [PDF]

				T. Takezako, C. Gogonea, Y. Saad, K. Noda, and S. S. Karnik "Network Leaning" as a Mechanism of Insurmountable Antagonism of the Angiotensin II Type 1 Receptor by Non-peptide Antagonists J. Biol. Chem., April 9, 2004; 279(15): 15248 - 15257. [Abstract] [Full Text] [PDF]

				A. C. Reid, C. J. Mackins, N. Seyedi, R. Levi, and R. B. Silver Coupling of angiotensin II AT1 receptors to neuronal NHE activity and carrier-mediated norepinephrine release in myocardial ischemia Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1448 - H1454. [Abstract] [Full Text] [PDF]

				T. Z. Dickson, J. Zagrobelny, C. C. Lin, M. A. Ritter, D. Snavely, D. Ramjit, S. Shahinfar, and M.-W. Lo Pharmacokinetics, Safety, and Antihypertensive Efficacy of Losartan in Combination with Hydrochlorothiazide in Hypertensive Patients with Renal Impairment J. Clin. Pharmacol., June 1, 2003; 43(6): 591 - 603. [Abstract] [Full Text] [PDF]

				R. Bravo, B. Somoza, M. Ruiz-Gayo, C. Gonzalez, L. M. Ruilope, and M. S. Fernandez-Alfonso Differential Effect of Chronic Antihypertensive Treatment on Vascular Smooth Muscle Cell Phenotype in Spontaneously Hypertensive Rats Hypertension, May 1, 2001; e10(5): . [Abstract] [Full Text] [PDF]

				G. Vauquelin, F. L. Fierens, Z. Gaborik, T. Le Minh, J.-P. De Backer, L. Hunyady, and P. M. Vanderheyden Role of basic amino acids of the human angiotensin type 1 receptor in the binding of the non-peptide antagonist candesartan Journal of Renin-Angiotensin-Aldosterone System, March 1, 2001; 2(1_suppl): S32 - S36. [Abstract] [PDF]

				F. L. Fierens, P. M. Vanderheyden, Z. Gaborik, T. Le Minh, J.-P. De Backer, L. Hunyady, A. Ijzerman, and G. Vauquelin Lys 199 mutation of the human angiotensin type 1 receptor differentially affects the binding of surmountable and insurmountable non-peptide antagonists Journal of Renin-Angiotensin-Aldosterone System, September 1, 2000; 1(3): 283 - 288. [Abstract] [PDF]

				S. S. Shetty and D. DelGrande Differential Inhibition of the Prejunctional Actions of Angiotensin II in Rat Atria by Valsartan, Irbesartan, Eprosartan, and Losartan J. Pharmacol. Exp. Ther., July 1, 2000; 294(1): 179 - 186. [Abstract] [Full Text]

				V. M Campese, Shaohua Ye, R. H Truong, and M. Gamburd Losartan reduces sympathetic nerve outflow from the brain of rats with chronic renal failure Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 202 - 208. [Abstract] [PDF]

				F. H. WAPSTRA, G. NAVIS, P. E. DE JONG, and D. DE ZEEUW Chronic Angiotensin II Infusion But Not Bradykinin Blockade Abolishes the Antiproteinuric Response to Angiotensin-Converting Enzyme Inhibition in Established Adriamycin Nephrosis J. Am. Soc. Nephrol., March 1, 2000; 11(3): 490 - 496. [Abstract] [Full Text] [PDF]

				P. Li, M. Fukuhara, D. I. Diz, C. M. Ferrario, and K. B. Brosnihan Novel Angiotensin II AT1 Receptor Antagonist Irbesartan Prevents Thromboxane A2-Induced Vasoconstriction in Canine Coronary Arteries and Human Platelet Aggregation J. Pharmacol. Exp. Ther., January 1, 2000; 292(1): 238 - 246. [Abstract] [Full Text]

				J. J. Lynch Jr., G. L. Stump, A. A. Wallace, C. A. Painter, J. M. Thomas, S. E. Kusma, R. J. Gould, and W. Grossman EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischemic ventricular arrhythmias in a canine model of recent myocardial infarction J. Am. Coll. Cardiol., September 1, 1999; 34(3): 876 - 884. [Abstract] [Full Text] [PDF]

				P. Morsing, G. Adler, U. Brandt-Eliasson, L. Karp, K. Ohlson, L. Renberg, P.-O. Sjoquist, and T. Abrahamsson Mechanistic Differences of Various AT1-Receptor Blockers in Isolated Vessels of Different Origin Hypertension, June 1, 1999; 33(6): 1406 - 1413. [Abstract] [Full Text] [PDF]

				L. Mazzolai, M. Maillard, J. Rossat, J. Nussberger, H. R. Brunner, and M. Burnier Angiotensin II Receptor Blockade in Normotensive Subjects : A Direct Comparison of Three AT1 Receptor Antagonists Hypertension, March 1, 1999; 33(3): 850 - 855. [Abstract] [Full Text] [PDF]

				R. Toto, P. Shultz, L. Raij, H. Mitchell, W. Shaw, D. Ramjit, J. Toh, and S. Shahinfar Efficacy and Tolerability of Losartan in Hypertensive Patients With Renal Impairment Hypertension, February 1, 1998; 31(2): 684 - 691. [Abstract] [Full Text] [PDF]

				G. A. Rongen, S. C. Brooks, S.-i. Ando, H. R. Dajani, B. L. Abramson, and J. S. Floras Neural and Hypotensive Effects of Angiotensin II Receptor Blockade Hypertension, January 1, 1998; 31(1): 378 - 383. [Abstract] [Full Text] [PDF]

				D. E Newby, S. Masumori, N. R Johnston, N. A Boon, and D. J Webb Endogenous angiotensin II contributes to basal peripheral vascular tone in sodium deplete but not sodium replete man Cardiovasc Res, November 1, 1997; 36(2): 268 - 275. [Abstract] [Full Text] [PDF]

				P. Li, C. M. Ferrario, and K. B. Brosnihan J. Pharmacol. Exp. Ther., June 1, 1997; 281(3): 1065 - 1070. [Abstract] [Full Text]

				B. A. Soffer, J. T. Wright Jr, J. H. Pratt, B. Wiens, A. I. Goldberg, and C. S. Sweet Effects of Losartan on a Background of Hydrochlorothiazide in Patients With Hypertension Hypertension, July 1, 1995; 26(1): 112 - 117. [Abstract] [Full Text]

				A. H. Gradman, K. E. Arcuri, A. I. Goldberg, L. S. Ikeda, E. B. Nelson, D. B. Snavely, and C. S. Sweet A Randomized, Placebo-Controlled, Double-Blind, Parallel Study of Various Doses of Losartan Potassium Compared With Enalapril Maleate in Patients With Essential Hypertension Hypertension, June 1, 1995; 25(6): 1345 - 1350. [Abstract] [Full Text]

				N. Basso, M. L. Kurnjek, P. Ruiz, and M. A. Cannata Effect of EXP 3174 on Blood Pressure of Normoreninemic Renal Hypertensive Rats Hypertension, February 1, 1995; 25(2): 283 - 287. [Abstract] [Full Text]

				M. R. Goldberg, T. E. Bradstreet, E. J. McWilliams, W. K. Tanaka, S. Lipert, T. D. Bjornsson, S. A. Waldman, B. Osborne, L. Pivadori, G. Lewis, et al. Biochemical Effects of Losartan, a Nonpeptide Angiotensin II Receptor Antagonist, on the Renin-Angiotensin-Aldosterone System in Hypertensive Patients Hypertension, January 1, 1995; 25(1): 37 - 46. [Abstract] [Full Text]

				M. Shou, R. Dai, D. Cui, K. R. Korzekwa, T. A. Baillie, and T. H. Rushmore A Kinetic Model for the Metabolic Interaction of Two Substrates at the Active Site of Cytochrome P450 3A4 J. Biol. Chem., January 12, 2001; 276(3): 2256 - 2262. [Abstract] [Full Text] [PDF]