JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nishikibe, M.
Right arrow Articles by Siegl, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nishikibe, M.
Right arrow Articles by Siegl, P.

Vol. 289, Issue 3, 1262-1270, June 1999

Pharmacological Properties of J-104132 (L-753,037), a Potent, Orally Active, Mixed ETA/ETB Endothelin Receptor Antagonist

M. Nishikibe, H. Ohta, M. Okada, K. Ishikawa, T. Hayama, T. Fukuroda, K. Noguchi, M. Saito, T. Kanoh, S. Ozaki, T. Kamei, K. Hara, D. William, S. Kivlighn, S. Krause, R. Gabel, G. Zingaro, N. Nolan, J. O'Brien, F. Clayton, J. Lynch, D. Pettibone and P. Siegl

Tsukuba Research Institutes and Development Research Laboratories, Banyu Pharmaceutical Co., Ltd., Ibaraki, Japan; and Merck Research Laboratories, West Point, Pennsylvania

J-104132 [(+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic; also referred to as L-753,037] is a potent, selective inhibitor of ETA and ETB endothelin (ET) receptors (e.g., Ki: cloned human ETA = 0.034 nM; cloned human ETB = 0.104 nM). In both ligand-binding and isolated tissue preparation protocols, the inhibition of ET receptors with J-104132 is reversible and competitive. In vitro, J-104132 is a potent antagonist of ET-1-induced accumulation of [3H]inositol phosphates in Chinese hamster ovary cells stably expressing cloned human ETA receptors (IC50 = 0.059 nM), ET-1-induced contractions in rabbit iliac artery (pA2 = 9.70) and of BQ-3020-induced contractions in pulmonary artery (pA2 = 10.14). J-104132 is selective for ET receptors because it had no effect on contractions elicited by norepinephrine or KCl in the vascular preparations. The in vivo potency of J-104132 was assessed using challenges with exogenous ET-1. In conscious mice, 5 nmol/kg i.v. ET-1 causes death. Pretreatment with J-104132 prevents the lethal response to ET-1 when administered i.v. (ED50 = 0.045 mg/kg) or p.o. in fed animals (ED50 = 0.35 mg/kg). In conscious, normotensive rats, pressor responses to 0.5 nmol/kg i.v. ET-1 are inhibited by J-104132 after i.v. (0.1 mg/kg) or p.o. (1 mg/kg) administration. In anesthetized dogs, ET-1 was administered directly into the renal artery or brachial artery to generate dose-response (blood flow) curves, and the inhibitory potency of J-104132 (i.v. infusion) was quantified. J-104132 produced greater than 10-fold shifts in the ET-1 dose-response curves at 0.03 mg/kg/h (renal) and 0.3 mg/kg/h (brachial). Oral bioavailability of J-104132 in rats was approximately 40%. These studies indicate that J-104132 is a selective, potent, orally active antagonist of both ETA and ETB receptors and is an excellent pharmacological tool to explore the therapeutic use of a mixed ETA/ETB receptor antagonist.

0022-3565/99/2893-1262$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 Circ. Res.Home page
M. Oka, N. Homma, L. Taraseviciene-Stewart, K. G. Morris, D. Kraskauskas, N. Burns, N. F. Voelkel, and I. F. McMurtry
Rho Kinase-Mediated Vasoconstriction Is Important in Severe Occlusive Pulmonary Arterial Hypertension in Rats
Circ. Res., March 30, 2007; 100(6): 923 - 929.
[Abstract] [Full Text] [PDF]

Home page
 HeartHome page
N F Kelland and D J Webb
Clinical trials of endothelin antagonists in heart failure: publication is good for the public health
Heart, January 1, 2007; 93(1): 2 - 4.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
K. Tadano, J. Suzuki, K. Hanada, M. Nakao, R. Nakao, S. Uehara, H. Ohta, T. Miyauchi, and M. Nishikibe
Pathophysiological Roles of Endogenous Endothelin-1 in Dogs with Chronic Heart Failure Produced by Rapid Right Ventricular Pacing
J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 729 - 736.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
S. Aleksic, Z. Szabo, U. Scheffel, H. T. Ravert, W. B. Mathews, L. Kerenyi, P. A. Rauseo, R. E. Gibson, H. D. Burns, and R. F. Dannals
In Vivo Labeling of Endothelin Receptors with [11C]L-753,037: Studies in Mice and a Dog
J. Nucl. Med., August 1, 2001; 42(8): 1274 - 1280.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
H. Hirose, I. Aoki, T. Kimura, T. Fujikawa, T. Numazawa, K. Sasaki, A. Sato, T. Hasegawa, M. Nishikibe, M. Mitsuya, et al.
Pharmacological Properties of (2R)-N-[1-(6-Aminopyridin-2-ylmethyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2- hydroxy-2-phenylacetamide: A Novel Muscarinic Antagonist with M2-Sparing Antagonistic Activity
J. Pharmacol. Exp. Ther., April 12, 2001; 297(2): 790 - 797.
[Abstract] [Full Text]

Home page
 Cardiovasc ResHome page
Y.-T. Shen, P. S Buie, J. J Lynch, S. M Krause, and X.-L. Ma
Chronic therapy with an ETA/B receptor antagonist in conscious dogs during progression of congestive heart failure: Intracellular Ca2+ regulation and nitric oxide mediated coronary relaxation
Cardiovasc Res, November 1, 2000; 48(2): 332 - 345.
[Abstract] [Full Text] [PDF]

Home page
 HypertensionHome page
T. Ikeda, H. Ohta, M. Okada, N. Kawai, R. Nakao, P. K. S. Siegl, T. Kobayashi, S. Maeda, T. Miyauchi, and M. Nishikibe
Pathophysiological Roles of Endothelin-1 in Dahl Salt-Sensitive Hypertension
Hypertension, September 1, 1999; 34(3): 514 - 519.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics.