Abstract
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 pED50 of 8.54 and 8.11 compared to a pED50 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 t1/2 of 5.5 h for 10 and 15. Compounds 10 and 15 bind specifically to rabbit antral smooth muscle motilin receptors with pIC50 values of 8.52 and 8.70.
MeSH terms
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Animals
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / metabolism
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Anti-Bacterial Agents / pharmacology
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Drug Design
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Drug Stability
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Duodenum / drug effects
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Duodenum / physiology
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Erythromycin / analogs & derivatives*
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Erythromycin / chemical synthesis
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Erythromycin / chemistry
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Erythromycin / metabolism
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Erythromycin / pharmacology
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Escherichia coli / drug effects
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Hydrogen-Ion Concentration
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In Vitro Techniques
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Male
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Models, Molecular
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Molecular Conformation
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Muscle Contraction / drug effects
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Pyloric Antrum / metabolism
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Rabbits
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Receptors, Gastrointestinal Hormone / metabolism
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Receptors, Neuropeptide / metabolism
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Staphylococcus aureus / drug effects
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Stereoisomerism
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Streptococcus / drug effects
Substances
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9-deoxo-4''-deoxy-3'-N--desmethyl-3'-N-ethanol-6,9-epoxyerythromycin A
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9-deoxo-4''-deoxy-3'-N-desmethyl-3'-ethyl-6,9-epoxyerythromycin A
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Anti-Bacterial Agents
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Receptors, Gastrointestinal Hormone
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Receptors, Neuropeptide
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motilin receptor
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Erythromycin