Design, synthesis and biological evaluation of pyridine-phenylpiperazines:A novel series of potent and selective alpha(1a)-adrenergic receptor antagonist

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 the R-hydroxy enant iomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers displayed comparable potency and better selectivity at alpha(1a)-AR. The S -hydroxy enantiomer 17 (K-i = 0.79 nM; alpha(1b)/alpha(1a) = 800; alpha(1d) /alpha(1a) = 104) was slightly less potent but much more selective at alpha (1a)-AR than tamsulosin (K-i = 0.13 nM, alpha(1b)/alpha(1a) = 15, alpha(1d) /alpha(1a) = 1.4). Compound 17 displayed higher selectivity in inhibiting r at prostate contraction over rat aorta contraction and also exhibited a hig her degree of uroselectivity than tamsulosin in the anesthetized dog model. (C) 2000 Elsevier Science Ltd. All rights reserved.