title: Synthesis of 4"-deoxy motilides: identification of a potent and orally active prokinetic drug candidate.
abstract: 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.
authors.affiliation: Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Lartey
authors.forename: H N
authors.initials: HN
authors.lastname: Nellans
authors.forename: R
authors.initials: R
authors.lastname: Faghih
authors.forename: A
authors.initials: A
authors.lastname: Petersen
authors.forename: C M
authors.initials: CM
authors.lastname: Edwards
authors.forename: L
authors.initials: L
authors.lastname: Freiberg
authors.forename: S
authors.initials: S
authors.lastname: Quigley
authors.forename: K
authors.initials: K
authors.lastname: Marsh
authors.forename: L L
authors.initials: LL
authors.lastname: Klein
authors.forename: J J
authors.initials: JJ
authors.lastname: Plattner
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D011817:Rabbits
chemical_list: C114264:Alemcinal; D004917:Erythromycin