title: Synthesis and structure-activity relationships in a series of ethenesulfonamide derivatives, a novel class of endothelin receptor antagonists.
abstract: 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.
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: T
authors.initials: T
authors.lastname: Tokunaga
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; D001794:Blood Pressure / Q000187:drug effects; D019556:COS Cells; D003001:Cloning, Molecular; D003655:Decerebrate State; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins / Q000037:antagonists & inhibitors; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011498:Protein Precursors / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides