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

被引：37

作者：

Elworthy, TR ^{[1
]}

Ford, APDW ^{[1
]}

Bantle, GW ^{[1
]}

Morgans, DJ ^{[1
]}

Ozer, RS ^{[1
]}

Palmer, WS ^{[1
]}

Repke, DB ^{[1
]}

Romero, M ^{[1
]}

Sandoval, L ^{[1
]}

Sjogren, EB ^{[1
]}

Talamas, FX ^{[1
]}

Vazquez, A ^{[1
]}

Wu, H ^{[1
]}

Arredondo, NF ^{[1
]}

Blue, DR ^{[1
]}

DeSousa, A ^{[1
]}

Gross, LM ^{[1
]}

Kava, MS ^{[1
]}

Lesnick, JD ^{[1
]}

Vimont, RL ^{[1
]}

Williams, TJ ^{[1
]}

Zhu, QM ^{[1
]}

Pfister, JR ^{[1
]}

Clarke, DE ^{[1
]}

机构：

[1] ROCHE BIOSCI, BIOL RES CTR, PALO ALTO, CA 94304 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1997年 / 40卷 / 17期

关键词：

D O I：

10.1021/jm970166j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Novel arylpiperazines were identified as alpha(1)-adrenoceptor(BR) 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, I,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;a 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 (pA(2) values: 8.8, 10.7, 9.3, and 9.9, respectively) and displaying 2-3 orders of magnitude selectivity over the alpha(1D)-AR.

引用

页码：2674 / 2687

页数：14

共 51 条

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