Design, synthesis, and structure-activity relationships of phthalimide-phenylpiperazines: A novel series of potent and selective alpha(1a)-adrenergicreceptor antagonists

Beginning from the screening hit and literature alpha(1)-adrenergic compoun ds, a hybridized basic skeleton A was proposed as the pharmacophore for pot ent and selective alpha(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 alpha(1a)-AR antagon ists were discovered. In all cases, binding affinity and selectivity at the alpha(1a)-AR of S-hydroxy enantiomers were higher than those of the R-hydr oxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy en antiomers had slightly lower binding affinity at alpha(1a)-AR but gained mo re than 2-fold selectivity for alpha(1a)-AR over alpha(1b)-AR, and 2- to 6- fold selectivity for alpha(1a)-AR over alpha(1d)-AR. They also had less cro ss 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; alpha(1b)/alpha(1a) >5690, >6060; alpha(1d)/alpha(1a) = 186, 158, respectively) were slightly l ess potent but much more selective at alpha(1a)-AR than tamsulosin (K-i = 0 .13 nM, alpha(1d)/alpha(1a)= 14.8, alpha(1d)/alpha(1a) = 1.4). In the funct ional assay, the S-hydroxy enantiomers 20, 23, and 24 were less potent than tamsulosin in inhibiting contractions of rat prostate tissue but more sele ctive in the inhibition of tissue contractions of rat prostate versus rat a orta. Compound 24 was selected as the development candidate for the treatme nt of BPH.