Discovery of heteroaryl sulfonamides as new EP1 receptor selective antagonists.
4-({2-[Isobutyl(phenylsulfonyl)amino]-5-(trifluoromethyl)phenoxy}methyl)benzoic acid (1) is a functional PGE2 antagonist selective for EP1 receptor subtype. Analogs of 1, in which the phenyl-sulfonyl moiety has been replaced with more hydrophilic heteroarylsulfonyl moieties, exhibited more optimized antagonist activity, while some of them showed in vivo antagonist activity. Structure-activity relationship (SAR) studies are also presented.
Naganawa
Atsushi
A
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. naganawa@ono.co.jp
Matsui
Toshiaki
T
Saito
Tetsuji
T
Ima
Masaki
M
Tatsumi
Tadashi
T
Yamamoto
Shingo
S
Murota
Masayuki
M
Yamamoto
Hiroshi
H
Maruyama
Takayuki
T
Ohuchida
Shuichi
S
Nakai
Hisao
H
Kondo
Kigen
K
Toda
Masaaki
M
D000527:Alprostadil / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002855:Chromatography, Thin Layer; D006224:Cricetinae; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D010084:Oxidation-Reduction; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects
D007202:Indicators and Reagents; D018078:Receptors, Prostaglandin E; D013449:Sulfonamides; C016767:sulprostone; D000527:Alprostadil; D015232:Dinoprostone