N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists

J Med Chem. 1997 Aug 15;40(17):2674-87. doi: 10.1021/jm970166j.


Novel arylpiperazines were identified as alpha 1-adrenoceptor (AR) subtype-selective antagonists by functional in vitro screening. 3-[4-(ortho-Substituted phenyl)piperazin-1-yl]propylamines were derivatized with N,N-dimethyl anthranilamides, nicotinamides, as well as carboxamides of quinoline, 1,8-naphthyridine, pyrazolo[3,4-b]pyridine, isoxazolo[3,4-b]pyridine, imidazo[4,5-b]pyridine, and pyrazolo[1,5-a]pyrimidines. Strips of rabbit bladder neck were employed as a predictive assay for antagonism in the human lower tract. Rings of rat aorta were used as a "negative screen" for the test antagonists. Binding to alpha 1-ARs was relatively sensitive to size and electronic features of the arylpiperazine portion of the antagonists and permissive to these features on the heteroaryl carboxamide side. These structure-affinity findings were exploited to produce nicotinamides (e.g. 13ii and 25x) and pyrazolo[3,4-b]pyridines (e.g. 37f and 37y) ligands with nanomolar affinity at the alpha 1-AR subtype prevalent in the human lower urinary tract(pA2 values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha 1D-AR.

MeSH terms

  • Adolescent
  • Adrenergic alpha-1 Receptor Antagonists*
  • Adrenergic alpha-Antagonists / chemical synthesis*
  • Adrenergic alpha-Antagonists / pharmacology
  • Adrenergic alpha-Antagonists / therapeutic use
  • Adult
  • Aged
  • Amides / chemical synthesis*
  • Amides / pharmacology
  • Amides / therapeutic use
  • Animals
  • Binding, Competitive
  • Humans
  • Male
  • Middle Aged
  • Models, Chemical
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • Piperazines / chemical synthesis*
  • Piperazines / pharmacology
  • Piperazines / therapeutic use
  • Prazosin / metabolism
  • Propylamines / chemical synthesis*
  • Propylamines / pharmacology
  • Propylamines / therapeutic use
  • Prostatic Hyperplasia / drug therapy
  • Rabbits
  • Rats
  • Structure-Activity Relationship
  • Urinary Bladder / drug effects*
  • Urinary Bladder / metabolism


  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic alpha-Antagonists
  • Amides
  • Piperazines
  • Propylamines
  • Prazosin