Pharmacological properties of J-104132 (L-753,037), a potent, orally active, mixed ETA/ETB endothelin receptor antagonist

J-104132 [(+)-(5S,6R,7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4- methoxyphen yl]-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2b]pyridine-6-carboxylic; al so referred to as L-753,037] is a potent, selective inhibitor of ETA and ET B endothelin (ET) receptors (e.g., K-i: cloned human ETA = 0.034 nM; cloned human ETB = 0.104 nM). In both ligand-binding and isolated tissue preparat ion protocols, the inhibition of ET receptors with J-104132 is reversible a nd competitive. In vitro, J-104132 is a potent antagonist of ET-1-induced a ccumulation of rf-l]inositol phosphates in Chinese hamster ovary cells stab ly expressing cloned human ETA receptors (IC50 = 0.059 nM), ET-1-induced co ntractions in rabbit iliac artery (pA(2) = 9.70) and of BQ-3020-induced con tractions in pulmonary artery (pA(2) = 10.14). J-104132 is selective for ET receptors because it had no effect on contractions elicited by norepinephr ine or KCI in the vascular preparations. The in vivo potency of J-104132 wa s 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 r esponse 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, presser respo nses 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 admini stered directly into the renal artery or brachial artery to generate dose-r esponse (blood flow) curves, and the inhibitory potency of J-104132 (i.v, i nfusion) was quantified. J-104132 produced greater than 10-fold shifts in t he ET-1 dose-response curves at 0.03 mg/kg/h (renal) and 0.3 mg/kg/h (brach ial). Oral bioavailability of J-104132 in rats was approximately 40%. These studies indicate that J-104132 is a selective, potent, orally active antag onist of both ETA and ETB receptors and is an excellent pharmacological too l to explore the therapeutic use of a mixed ETA/ ETB receptor antagonist.