title: Design, synthesis and biological evaluation of pyridine-phenylpiperazines: a novel series of potent and selective alpha1a-adrenergic receptor antagonist.
abstract: Beginning from the screening hit and literature alpha1-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective alpha1a-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 alpha1a-AR antagonists were discovered. In all cases, binding affinity and selectivity at the alpha1a-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 alpha1a-AR. The S-hydroxy enantiomer 17 (Ki = 0.79 nM; alpha1b/alpha1a = 800; alpha1d/alpha1a = 104) was slightly less potent but much more selective at alpha1a-AR than tamsulosin (Ki = 0.13 nM, alpha1b/alpha1a = 15, alpha1d/alpha1a = 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.
authors.affiliation: Drug Discovery Division, The R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869, USA. gkuo@prius.jnj.com
authors.forename: G H
authors.initials: GH
authors.lastname: Kuo
authors.forename: C
authors.initials: C
authors.lastname: Prouty
authors.forename: W V
authors.initials: WV
authors.lastname: Murray
authors.forename: V
authors.initials: V
authors.lastname: Pulito
authors.forename: L
authors.initials: L
authors.lastname: Jolliffe
authors.forename: P
authors.initials: P
authors.lastname: Cheung
authors.forename: S
authors.initials: S
authors.lastname: Varga
authors.forename: M
authors.initials: M
authors.lastname: Evangelisto
authors.forename: C
authors.initials: C
authors.lastname: Shaw
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008297:Male; D023421:Models, Animal; D009119:Muscle Contraction / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D018340:Receptors, Adrenergic, alpha-1; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D000077409:Tamsulosin; D014662:Vasoconstrictor Agents / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D011725:Pyridines; D018340:Receptors, Adrenergic, alpha-1; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D000077409:Tamsulosin; C031503:phenylpiperazine; C023666:pyridine