Ethenesulfonamide Derivatives, a Novel Class of Orally Active Endothelin-A Receptor Antagonists
Year: 2001
Type: article
Abstract: In the present article we wish to report the discovery of a novel class of ET(A)-selective endothelin (ET) receptor antagonists through the modification of the ET(A)/ET(B) non-selective antagonist, Ro47-0203 (Bosentan, 1). Replacement of the benzenesulfonamide group of 1 with a 2-phenylethenesulfonamide group gave compound 5a and resulted in improvement in ET(A)-selectivity. Optimization of the alkoxy side chain attached to the core pyrimidine ring yielded the 2-fluoroethoxy derivative (5n) with further improvement of ET(A)-selectivity. [IC50=2.1 nM for ET(A) receptor, ET(B)/ET(A) ratio=1200]. After oral administration, compound 5n inhibited the big ET-1 induced pressor response in pithed rats with a DR2 value of 2.6 mg/kg and also exhibited a potent antagonistic activity in conscious rats.
DOI: 10.1248/cpb.49.606
Authors: Hironori HARADA, Jun-ichi KAZAMI, Susumu WATANUKI, Ryuji TSUZUKI, Katsumi SUDOH, Akira FUJIMORI, Akihiro TANAKA, Shin-ichi TSUKAMOTO, Isao YANAGISAWA
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2005758547