Quantitative Structure-activity Relationship Study of Novel α_1a-selective Adrenoceptor Antagonists

Abstract

Two series of compounds were recently reported as novel α_1a-selective adrenoceptor antagonists. In the first series, a dihydropyrimidone moiety is attached to a 4-phenyl piperidine containing side chain, while in the second, it is linked to a 4-substituted phenyl piperazine containing side chain. These compounds having potential for the treatment of benign prostatic hyperplasia, a urological disorder in the older age male population, were subjected to a quantitative structure-activity relationship study. The analysis has helped to ascertain the role of different substituents in explaining the observed binding potencies of these analogues. In the first category of compounds, three sites R₁ R2 and X were varied and from the quantitative structure - activity relationship, it emerged that X- and R₁-substituents having respectively, the high values of field and resonance effects may lead to more potent α_1a-antagonists. The substituent of R₂ being either CH₃ or C₂H₅, does not add to improve the activity and thus the site, at present, becomes redundant. This site may, however, be explored for some additional substituents in future. In the second series of compounds, the phenyl ring, linked to a piperazine moiety at the end of a side chain, was substituted with various groups onto different positions. From derived significant correlations, it appeared the less polar and/or bulky substituents at the meta- and para-positions and a more hydrophobic substituent at the para-position are advantageous.

Key Words:

• Quantitative structure-activity relationship (QSAR)
• Selective antagonists of α_1a-adrenoceptor
• Hansen analysis
• Analogues of dihydropyrimidone