New ether oxime derivatives of erythromycin A. A structure-activity relationship study.
The discovery of roxithromycin is the result of a rational and scientific process, based on the fact that at least one reason for erythromycin A's resorption variability after oral administration was its instability in the gastric juice. This instability is due to the reactivity of the ketone in position 9 in acidic medium and one chemical approach was to mask it by an oxime function. Both stereoisomers of this oxime were isolated. Direct O-alkylation of this oxime allowed access to various ether oxime derivatives and of the latter the E stereoisomers were more interesting than the Z ones. The choice of the nature of the oxime substitution was made according to the lipophilic or hydrophilic character of the aliphatic ether chain and these alterations were mainly carried out by introducing heteroatoms into this chain. These different derivatives were classified in 5 groups according to the chemical nature of the chain: Aliphatic, aromatic and nitrogen-, oxygen- and sulfur-containing chains. Two classes, those containing a nitrogen or an oxygen in the ether side chains, showed differential in vitro/in vivo antibiotic activities, with improved bioavailability. Some preliminary pharmacokinetic data confirmed this improvement and led to the selection of five candidates, from which roxithromycin emerged as the best compound.
Gasc
J C
JC
Centre de Recherches Roussel Uclaf, Romainville, France.
d'Ambrieres
S G
SG
Lutz
A
A
Chantot
J F
JF
D000818:Animals; D001419:Bacteria / Q000187:drug effects*; D001682:Biological Availability; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D015575:Roxithromycin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013237:Stereoisomerism; D013290:Streptococcal Infections / Q000188:drug therapy*; D013329:Structure-Activity Relationship
D015575:Roxithromycin; D004917:Erythromycin