- 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 furhther 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 39percent 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 (1,4percent) oral bioavailability.
- Lartey, Paul A.,Nellans, Hugh N.,Faghih, Ramin,Petersen, Albert,Edwards, Carla M.,et al.
-
-
Read Online
- Facile N-demethylation of erythromycins
-
4-Deoxyerythromycin B reacts with 1-chloroethyl chloroformate to give the corresponding N-demethyl N-chloroethyl carbamate. Mild methanolysis removes the chloroethyl group giving the N-demethyl erythromycin derivative while also forming the 6,9-enol ether moiety. Further manipulation gives ABT- 229, a potential prokinetic agent.
- Hengeveld, John E.,Gupta, Ashok K.,Kemp, Anne H.,Thomas, Albert V.
-
-
Read Online