Hwan-Soo Jae

Pharmacology of endothelin receptor antagonists ABT-627, ABT-546, A-182086 and A-192621: ex vivo and in vivo studies.

Endothelins (ETs), 21-amino-acid peptides involved in the pathogenesis of various diseases, bind to ET(A) and ET(B) receptors to initiate their effects. Based on the same core structure, we have developed four small-molecule ET receptor antagonists, ABT-627 (atrasentan), ABT-546, A-182086 and A-192621, which exhibit differences in selectivity for ET(A) and ET(B) receptors. In this report, we compare the efficacy, potency and pharmacokinetic properties of these four antagonists, including potency in inhibiting ET-1- or Sarafotoxin 6c-induced vessel constriction in isolated arteries and efficacy in antagonizing ET-1-, big ET-1- or Sarafotoxin 6c-induced pressor responses in rats.

5-Membered ring heterocyclic carboxylic acids as angiotensin II antagonists

A series of 5-membered ring heterocyclic analogs of A-81988 were synthesized in order to determine their activity as angiotensin II antagonists. The activity of these compounds in a rabbit aorta in vitro assay ranged from pA2 values of <6 to 9.3, with the thiazole, thiadiazole and triazole heterocycles being more potent A-II antagonists than the imidazole and pyrazole derivatives. The best activity was seen with the triazole 9b which had a pA2 of 9.3.