Synthesis of 9-deoxo-4''-deoxy-6,9-epoxyerythromycin derivatives: novel and acid-stable motilides.
In our quest toward the discovery of highly potent and acid-stable motilides, novel 4"-deoxy derivatives of 9-deoxo-6, 9-epoxyerythromycin were designed, synthesized, and evaluated for their gastrointestinal prokinetic activities. These compounds, in their 9R configuration, were more potent than their 6,9-enol ether homologues in inducing well-coordinated smooth muscle contractions in an in vitro rabbit duodenal assay: e.g., (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethyl-6, 9-epoxyerythromycin A (10) and (9R), (8S)-9-deoxo-4"-deoxy-3'-N-desmethyl-3'-N-ethanol-6, 9-epoxyerythromycin A (15) had a pED50 of 8.54 and 8.11 compared to a pED50 of 7.22 for compound 2 (ABT-229). Reduction of the 6,9-enol ether, which was aimed at improving the acid stability, afforded the most stable motilides to date with t1/2 of 5.5 h for 10 and 15. Compounds 10 and 15 bind specifically to rabbit antral smooth muscle motilin receptors with pIC50 values of 8.52 and 8.70.
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
R
R
Faghih
P A
PA
Lartey
H N
HN
Nellans
L
L
Seif
C
C
Burnell-Curty
L L
LL
Klein
P
P
Thomas
A
A
Petersen
A
A
Borre
T
T
Pagano
K H
KH
Kim
M
M
Heindel
Y L
YL
Bennani
J J
JJ
Plattner
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004355:Drug Stability; D004386:Duodenum / Q000187:drug effects / Q000502:physiology; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011706:Pyloric Antrum / Q000378:metabolism; D011817:Rabbits; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D013291:Streptococcus / Q000187:drug effects
C114183:9-deoxo-4''-deoxy-3'-N--desmethyl-3'-N-ethanol-6,9-epoxyerythromycin A; C114182:9-deoxo-4''-deoxy-3'-N-desmethyl-3'-ethyl-6,9-epoxyerythromycin A; D000900:Anti-Bacterial Agents; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; C050802:motilin receptor; D004917:Erythromycin