Synthesis of 9-Deoxo-4‘‘-deoxy-6,9-epoxyerythromycin Derivatives: Novel and Acid-Stable Motilides

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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.

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