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 activi ty, novel 4''-deoxy derivatives of 8,9-anhydroerythromycin 6,9-hemiace tal were designed, synthesized, and evaluated for their gastrointestin al prokinetic activities. These compounds were orders of magnitude mor e potent than their 4''-hydroxy analogs in inducing smooth muscle cont ractions in an in vitro rabbit duodenal assay. Removal of the 12-hydro xy group, which was aimed at improving oral bioavailability, also affo rded further potentiation in in vitro activity, leading to the identif ication of ro-4''-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B 6,9-he miacetal (ABT-229) as a potential prokinetic drug. ABT-229 was >300 00 0 times more potent than erythromycin in, vitro and had 39% oral bioav ailability in dog compared to its 4'';12-dihydroxy congener (EM-523), which was only 400 times more potent than erythromycin and had relativ ely low (1.4%) oral bioavailability.