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.