title: Structure-activity relationship study of TXA2 receptor antagonists. 4-[2-(4-substituted phenylsulfonylamino)ethylthio]phenoxyacetic acids and related compounds.
abstract: We have recently reported that 4-[2-(4-substituted phenylsulfonylamino) ethylthio]phenoxyacetic acids and related compounds showed potent thromboxane A2 (TXA2) receptor antagonist activity. To understand how substituents affect the biological activity, the quantitative structure-activity relationship (QSAR) was analyzed by using the Hansch-Fujita method for 36 compounds, including newly synthesized compounds. The positive coefficient for pi R and FR in the results of the QSAR study suggested that a hydrophobic an sigma electron-withdrawing substituent R at the para-position of the phenylsulfonyl moiety is required to improve the activity. Further, a substituent R which is long and moderately wide, was suggested to be preferable for the activity. The positive coefficients for pi X,Y,W-COOH and sigma Q(1)-(6) may indicate that the introduction of a hydrophobic and electron-withdrawing group on the benzene ring of the phenoxy acetic acid moiety enhances the activity. The length of the W-COOH moiety may also be important. On the other hand, the effect of the presence of methylene (n = 1) was not clear.
authors.affiliation: Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Kawashima
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: S
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Shimazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Chiba
authors.forename: M
authors.initials: M
authors.lastname: Satake
authors.forename: C
authors.initials: C
authors.lastname: Iwata
authors.forename: K
authors.initials: K
authors.lastname: Hatayama
mesh_terms: D000818:Animals; D008297:Male; D010642:Phenoxyacetates / Q000138:chemical synthesis* / Q000494:pharmacology*; D011817:Rabbits; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D010642:Phenoxyacetates; D017482:Receptors, Thromboxane