Structure-activity relationship study of TXA2 receptor antagonists. 4-[2-(4-substituted phenylsulfonylamino)ethylthio]phenoxyacetic acids and related compounds.
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.
Kawashima
Y
Y
Research Center, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Sato
M
M
Yamamoto
S
S
Shimazaki
Y
Y
Chiba
Y
Y
Satake
M
M
Iwata
C
C
Hatayama
K
K
D000818:Animals; D008297:Male; D010642:Phenoxyacetates / Q000138:chemical synthesis* / Q000494:pharmacology*; D011817:Rabbits; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D010642:Phenoxyacetates; D017482:Receptors, Thromboxane