Further optimization of sulfonamide analogs as EP1 receptor antagonists: synthesis and evaluation of bioisosteres for the carboxylic acid group.
4-{[2-[(2-Furylsulfonyl)(isobutyl)amino]-5-(trifluoromethyl)phenoxy]methyl}benzoic acid analogs 2a and b and a series of the acid analogs, in which the carboxylic acid residue of 2b was replaced with various kinds of carboxylic acid bioisosteres, were synthesized and evaluated as EP1 receptor antagonists. Compound 2b and its monocyclic acid analogs, in which the carboxylic acid residue of 2b was replaced with monocyclic acid bioisosteres, were found to show potent EP1 receptor antagonist activity. Optimization of the linker Y between the phenyl moiety and the carboxylic acid residue of 2b was also carried out (Table 5). Compounds 2b and 16 and 17 possessing conformationally restricted linker Y were found to show the most optimized potency among the tested compounds. Cytochrome P450 inhibition of optimized compounds was also investigated. Details of the structure-activity relationship study are 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
Saito
Tetsuji
T
Murota
Masayuki
M
Aratani
Yoshiyuki
Y
Kijima
Hideomi
H
Yamamoto
Hiroshi
H
Maruyama
Takayuki
T
Ohuchida
Shuichi
S
Nakai
Hisao
H
Toda
Masaaki
M
D000818:Animals; D016466:CHO Cells; D002264:Carboxylic Acids / Q000737:chemistry*; D006224:Cricetinae; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013055:Spectrophotometry, Infrared; D013449:Sulfonamides / Q000494:pharmacology*
D002264:Carboxylic Acids; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013449:Sulfonamides