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Further optimization of sulfonamide analogs as EP1 receptor antagonists: synthesis and evaluation of bioisosteres for the carboxylic acid group.

Abstract：

: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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Naganawa A,Matsui T,Ima M,Saito T,Murota M,Aratani Y,Kijima H,Yamamoto H,Maruyama T,Ohuchida S,Nakai H,Toda M

doi

10.1016/j.bmc.2006.06.067

subject

Has Abstract

pub_date

2006-11-01 00:00:00

pages

7121-37

issue

21

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(06)00543-8

journal_volume

14

pub_type

杂志文章

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