title: Design, synthesis, and structure-activity relationships of phthalimide-phenylpiperazines: a novel series of potent and selective alpha(1)(a)-adrenergic receptor antagonists.
abstract: Beginning from the screening hit and literature alpha(1)-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent 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 antagonists 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-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers had slightly lower binding affinity at alpha(1a)-AR but gained more 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 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; alpha(1b)/alpha(1a) >5690, >6060; alpha(1d)/alpha(1a) = 186, 158, respectively) were slightly less potent but much more selective at alpha(1a)-AR than tamsulosin (K(i) = 0.13 nM, alpha(1b)/alpha(1a) = 14.8, alpha(1d)/alpha(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.
authors.affiliation: Drug Discovery Division, Analytical Development, Global Chemical & Pharmaceutical Development Division, The R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 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: J
authors.initials: J
authors.lastname: Wang
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D015195:Drug Design; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011470:Prostatic Hyperplasia / Q000188:drug therapy; D011869:Radioligand Assay; D051381:Rats; D020318:Rats, Long-Evans; D018340:Receptors, Adrenergic, alpha-1; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D010797:Phthalimides; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1