Design, synthesis, and structure-activity relationships of phthalimide-phenylpiperazines : A novel series of potent and selective α1a-Adrenergic receptor antagonists

Beginning from the screening hit and literature α 1 -adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective α 1a -AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective α 1a -AR antagonists were discovered. In all cases, binding affinity and selectivity at the α 1a -AR of S-hydroxy enantiomers were higher than those of the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers had slightly lower binding affinity at α 1a -AR but gained more than 2-fold selectivity for α 1a -AR over α 1b -AR, and 2- to 6-fold selectivity for α 1a -AR over α 1d -AR. They also had less cross activities against a panel of 25-35 peripheral and CNS receptors. The S-hydroxy enantiomers 23 and 24 (K i = 0.29 nM, 0.33 nM; α 1b /α 1a >5690, >6060; α 1d /α 1a = 186, 158, respectively) were slightly less potent but much more selective at α 1a -AR than tamsulosin (K i = 0.13 nM, α 1b /α 1a = 14.8, α 1d /α 1a = 1.4). In the functional assay, the S-hydroxy enantiomers 20, 23, and 24 were less potent than tamsulosin in inhibiting contractions of rat prostate tissue but more selective in the inhibition of tissue contractions of rat prostate versus rat aorta. Compound 24 was selected as the development candidate for the treatment of BPH.