N-Arylpiperazinyl-N‘-propylamino Derivatives of Heteroaryl Amides as Functional Uroselective α1-Adrenoceptor Antagonists
| Autor: | R.L. Vimont, Lisa M. Gross, Magarita Romero, David E. Clarke, Andrea DeSousa, Wylie Solang Palmer, Nicolas F. Arredondo, Francisco Xavier Talamas, Anthony P.D.W. Ford, D.R. Blue, Gary W. Bantle, Leticia Sandoval, David Bruce Repke, John D Lesnick, Rachel S. Ozer, Alfredo Vazquez, Eric Brian Sjogren, Timothy J. Williams, M. Shannon Kava, David J. Morgans, Quan-Ming Zhu, Helen Y. Wu, Todd R. Elworthy, and Jürg R. Pfister |
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| Rok vydání: | 1997 |
| Předmět: |
Adult
Male Adolescent Stereochemistry medicine.drug_class Urinary Bladder Prostatic Hyperplasia Carboxamide Binding Competitive Chemical synthesis Piperazines Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Pyridine medicine Animals Humans Propylamines Adrenergic alpha-Antagonists Aged Bicyclic molecule Quinoline Antagonist Muscle Smooth Prazosin Middle Aged Amides In vitro Rats Models Chemical chemistry Adrenergic alpha-1 Receptor Antagonists Molecular Medicine Rabbits |
| Zdroj: | Journal of Medicinal Chemistry. 40:2674-2687 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm970166j |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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