ChemInform Abstract: Ethenesulfonamide Derivatives, a Novel Class of Orally Active Endothelin-A Receptor Antagonists

Autor:	Susumu Watanuki, Akihiro Tanaka, Isao Yanagisawa, Katsumi Sudoh, Shin-ichi Tsukamoto, Akira Fujimori, Hironori Harada, Jun-Ichi Kazami, Ryuji Tsuzuki
Rok vydání:	2010
Předmět:	Pyrimidine Antagonist General Medicine Pharmacology Endothelin A Receptor Antagonists Bosentan chemistry.chemical_compound chemistry Oral administration medicine Receptor Endothelin receptor IC50 medicine.drug
Zdroj:	ChemInform. 32
ISSN:	1522-2667 0931-7597
DOI:	10.1002/chin.200146149
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::b153596b81e32e94947f9244b9571f4a https://doi.org/10.1002/chin.200146149 Zobrazit plný text záznamu Plný text