Synthesis of 9-deoxo-4"-deoxy-6,9-epoxyerythromycin derivatives:: Novel and acid-stable motilides

被引：13

作者：

Faghih, R ^{[1
]}

Lartey, PA ^{[1
]}

Nellans, HN ^{[1
]}

Seif, L ^{[1
]}

Burnell-Curty, C ^{[1
]}

Klein, LL ^{[1
]}

Thomas, P ^{[1
]}

Petersen, A ^{[1
]}

Borre, A ^{[1
]}

Pagano, T ^{[1
]}

Kim, KH ^{[1
]}

Heindel, M ^{[1
]}

Bennani, YL ^{[1
]}

Plattner, JJ ^{[1
]}

机构：

[1] Abbott Labs, Div Pharmaceut Discovery, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 18期

关键词：

D O I：

10.1021/jm980022k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In our quest toward the discovery of highly potent and acid-stable motilides, novel 4 "-deoxy derivatives of 9-deoxo-6,9-epoxyerythromycin were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds, in their 9R configuration, were more potent than their 6,9-enol ether homologues in inducing well-coordinated smooth muscle contractions in an in vitro rabbit duodenal assay: e.g., (9R),(8S)-9-deoxo-4 "-deoxy-3'-N-desmethyl-3'-N-ethyl-6,9-epoxyerythromycin A (10) and (9R),(8S)-9-deoxo-4 "'-deoxy-3'-N-desmethyl-3'-N-ethanol-6,9-epoxyerythromycin A (15) had a pED(50) Of 8.54 and 8.11 compared to a pED(50) Of 7.22 for compound 2 (ABT-229). Reduction of the 6,9-enol ether, which was aimed at improving the acid stability, afforded the most stable motilides to date with t(1/2) of 5.5 h for 10 and 15. Compounds 10 and 15 bind specifically to rabbit antral smooth muscle motilin receptors with pIC(50) values of 8.52 and 8.70.

引用

页码：3402 / 3408

页数：7

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