title: Optimization of sulfonamide derivatives as highly selective EP1 receptor antagonists.
abstract: A series of 4-[(2-{isobutyl[(5-methyl-2-furyl)sulfonyl]amino}phenoxy)methyl]benzoic acids and 4-({2-[isobutyl(1,3-thiazol-2-ylsulfonyl)amino]phenoxy}methyl)benzoic acids were synthesized and evaluated for their EP receptor affinities and EP1 receptor antagonist activities. Further structural optimization was carried out to reduce inhibitory activity against hepatic cytochrome P450 isozymes, which could represent a harmful potential drug interaction. Selected compounds were also evaluated for their binding affinities to hTP, hDP, mFP, and hIP, and for their hEP1 receptor antagonist activities. The results of structure-activity relationship studies are also presented.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. naganawa@ono.co.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Naganawa
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Matsui
authors.forename: Masaki
authors.initials: M
authors.lastname: Ima
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuruta
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hiroki
authors.initials: H
authors.lastname: Okada
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.forename: Hisao
authors.initials: H
authors.lastname: Nakai
authors.forename: Kigen
authors.initials: K
authors.lastname: Kondo
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D006801:Humans; D008099:Liver / Q000201:enzymology; D011485:Protein Binding; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001565:Benzoates; D065607:Cytochrome P-450 Enzyme Inhibitors; C545635:PTGER1 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013449:Sulfonamides