Synthesis of 4"-deoxy motilides: identification of a potent and orally active prokinetic drug candidate

As an approach to discovering highly potent motilides with oral activity, novel 4"-deoxy derivatives of 8,9-anhydroerythromycin 6,9-hemiacetal were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds were orders of magnitude more potent than their 4"-hydroxy analogs in inducing smooth muscle contractions in an in vitro rabbit duodenal assay. Removal of the 12-hydroxy group, which was aimed at improving oral bioavailability, also afforded further potentiation in in vitro activity, leading to the identification of 8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B 6,9-hemiacetal (ABT-229) as a potential prokinetic drug. ABT-229 was > 300,000 times more potent than erythromycin in vitro and had 39% oral bioavailability in dog compared to its 4",12-dihydroxy congener (EM-523), which was only 400 times more potent than erythromycin and had relatively low (1.4%) oral bioavailability.