title: Ethenesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.
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.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan. haradah@yamanouchi.co.jp
authors.forename: H
authors.initials: H
authors.lastname: Harada
authors.forename: J
authors.initials: J
authors.lastname: Kazami
authors.forename: S
authors.initials: S
authors.lastname: Watanuki
authors.forename: R
authors.initials: R
authors.lastname: Tsuzuki
authors.forename: K
authors.initials: K
authors.lastname: Sudoh
authors.forename: A
authors.initials: A
authors.lastname: Fujimori
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
authors.forename: S
authors.initials: S
authors.lastname: Tsukamoto
authors.forename: I
authors.initials: I
authors.lastname: Yanagisawa
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003655:Decerebrate State / Q000503:physiopathology; D065128:Endothelin Receptor Antagonists; D005260:Female; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D065128:Endothelin Receptor Antagonists; D007202:Indicators and Reagents; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides