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.
Lartey
P A
PA
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
Nellans
H N
HN
Faghih
R
R
Petersen
A
A
Edwards
C M
CM
Freiberg
L
L
Quigley
S
S
Marsh
K
K
Klein
L L
LL
Plattner
J J
JJ
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
C114264:Alemcinal; D004917:Erythromycin