ChemInform Abstract: Synthesis and Structure-Activity Relationships in a Series of Ethenesulfonamide Derivatives, a Novel Class of Endothelin Receptor Antagonists

Autor: Susumu Watanuki, Akihiro Tanaka, Akira Fujimori, Isao Yanagisawa, Ryuji Tsuzuki, Shin-ichi Tsukamoto, Jun-Ichi Kazami, Katsumi Sudoh, Tatsuhiro Tokunaga, Hironori Harada
Rok vydání: 2010
Předmět:
Zdroj: ChemInform. 33
ISSN: 1522-2667
0931-7597
DOI: 10.1002/chin.200217147
Popis: In the previous paper, we described a series of the 2-arylethenesulfonamide derivatives, a novel class of ETA-selective endothelin (ET) receptor antagonists, including the compounds 1a, b. Compound 1a showed excellent oral antagonistic activities and pharmacokinetic profiles, and the monopotassium salt of 1 (YM-598 monopotassium) is in clinical trials. In this paper, we wish to report the investigation of the further details of structure-activity relationships (SARs) of the 2-phenylethenesulfonamide region in 1a. It was found that methyl substitutions at the 2-, 4- and 6-positions of the phenyl group in 1a led to the discovery of the ET(A)/ET(B) mixed antagonist (6s) with an IC50 of 2.2 nM for the ET(A) receptor. We also found that introduction of an ethyl group to the 1-position of the ethenyl group in 1a gave the ET(A) selective antagonist (6u) with an oral endothelin antagonistic activity in rats.
Databáze: OpenAIRE
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