Optimization of sulfonamide derivatives as highly selective EP1 receptor antagonists.
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.
Naganawa
Atsushi
A
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. naganawa@ono.co.jp
Matsui
Toshiaki
T
Ima
Masaki
M
Yoshida
Koji
K
Tsuruta
Hiroshi
H
Yamamoto
Shingo
S
Yamamoto
Hiroshi
H
Okada
Hiroki
H
Maruyama
Takayuki
T
Nakai
Hisao
H
Kondo
Kigen
K
Toda
Masaaki
M
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*
D001565:Benzoates; D065607:Cytochrome P-450 Enzyme Inhibitors; C545635:PTGER1 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013449:Sulfonamides