Pharmacology of A-216546:: a highly selective antagonist for endothelin ETA receptor

Endothelins, 21-amino acid peptides involved in the pathogenesis of various diseases, bind to endothelin ETA and ETB receptors to initiate their effects. Here, we characterize the pharmacology of A-216546 ([2S-(2,2-dimethylpentyl)-4S-(7-methoxy-1,3-benzodioxol-5-yl)-1-(N,N-di(n-butyl) aminocarbonylmethyl)-pyrrolidine-3 R-carboxylic acid), a potent antagonist with > 25,000-fold selectivity for the endothelin ETA receptor. A-216546 inhibited [I-125]endothelin-1 binding to cloned human endothelin ETA and ETB receptors competitively with K-i of 0.45 and 13,000 nM, and blocked endothelin-1-induced arachidonic acid release and phosphatidylinositol hydrolysis with IC50 of 0.59 and 3 nM, respectively. In isolated vessels, A-216546 inhibited endothelin ETA receptor-mediated endothelin-l-induced vasoconstriction, and endothelin ETB receptor-mediated sarafotoxin 6c-induced vasoconstriction with pA(2) of 8.29 and 4.57, respectively. A-216546 was orally available in rat, dog and monkey. In vivo, A-216546 dose-dependently blocked endothelin-1-induced presser response in conscious rats. Maximal inhibition remained constant for at least 8 h after dosing. In conclusion, A-216546 is a potent, highly endothelin ETA receptor-selective and orally available antagonist, and will be useful for treating endothelin-1-mediated diseases. (C) 1999 Elsevier Science B.V. All rights reserved.