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 π_R and F_R in the results of the QSAR study suggested that a hydrophobic and σ 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 π_{X, Y, W-COOH} and ΣQ_(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.