In vitro and in vivo characterization of novel 8-methoxy derivatives of chlortetracycline.
The in vitro activities of three new 8-methoxychlortetracyclines, Sch 36969, 33256 and 34164 were compared to tetracycline, minocycline and doxycycline. Against aerobic Gram-negative rods Sch 36969 had a geometric mean MIC (GMM) of 4.2 micrograms/ml, about 8-fold more potent than Sch 33256, and similar to all the other compounds. Sch 36969 also had good activity against methicillin-resistant (GMM, 0.21 micrograms/ml) and -susceptible Staphylococci (GMM, 0.14 micrograms/ml), Streptococci (GMM, 0.06 micrograms/ml), and most anaerobic bacteria (GMM, less than 0.5 micrograms/ml). In general, Sch 36969 was similar to, or more potent than, all the other compounds tested. Serum levels of Sch 36969 in squirrel monkeys were 4-fold lower (AUC, 4.5 micrograms.hours/ml) than those of chlortetracycline (AUC, 16.1 micrograms.hours/ml). In mouse protection tests (PD50s) against various strains of bacteria, Sch 36969 was similar in activity to tetracycline, but up to 6-fold less active than chlortetracycline. The structure activity relationships for these new chlortetracyclines are described.
Cacciapuoti
A
A
Schering Corporation, Bloomfield, NJ 07003.
Moss
E L
EL
Menzel
F
F
Cramer
C A
CA
Weiss
W
W
Loebenberg
D
D
Hare
R S
RS
Miller
G H
GH
D000818:Animals; D002751:Chlortetracycline / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D012453:Saimiri; D013329:Structure-Activity Relationship; D013754:Tetracyclines / Q000097:blood / Q000494:pharmacology*
D013754:Tetracyclines; C054355:8-methoxychlortetracycline; C054353:dactylocyclinone; C054352:2'-N-methyl-8-methoxychlortetracycline; D002751:Chlortetracycline