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.
Faghih
R
R
Pharmaceutical Discovery Division, Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
Lartey
P A
PA
Nellans
H N
HN
Seif
L
L
Burnell-Curty
C
C
Klein
L L
LL
Thomas
P
P
Petersen
A
A
Borre
A
A
Pagano
T
T
Kim
K H
KH
Heindel
M
M
Bennani
Y L
YL
Plattner
J J
JJ
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