Design, synthesis and biological evaluation of pyridine-phenylpiperazines: A novel series of potent and selective α1a-adrenergic receptor antagonist

Abstract 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 the R -hydroxy enantiomers. As compared to the des-hydroxy analogues, the S -hydroxy enantiomers displayed comparable potency and better selectivity at α 1a -AR. The S -hydroxy enantiomer 17 ( K i =0.79 nM; α 1b α 1a =800 ; α 1d α 1a =104 ) was slightly less potent but much more selective at α 1a -AR than tamsulosin ( K i =0.13 nM, α 1b α 1a =15 , α 1d α 1a =1.4 ). Compound 17 displayed higher selectivity in inhibiting rat prostate contraction over rat aorta contraction and also exhibited a higher degree of uroselectivity than tamsulosin in the anesthetized dog model.