CP5484, a novel quaternary carbapenem with potent anti-MRSA activity and reduced toxicity.
A new series of 1beta-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus was prepared, and the activities of these compounds against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. To study the effect of basic moieties on anti-MRSA activity, we introduced an amino, or imino, or amidino group at the 6-position of imidazo[5,1-b]thiazole in place of the carbamoylmethyl moiety of CP5068. Anti-MRSA activities of almost all basic group-substituted carbapenems were improved, though some of the compounds showed stronger acute toxicity in mice than IPM. In order to decrease the toxicity without decreasing the activity, we introduced various additional functionalities around the basic moiety. Finally, we obtained CP5484, which has excellent anti-MRSA activity and low acute toxicity.
Maruyama
Takahisa
T
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. takahisa_maruyama@meiji.co.jp
Yamamoto
Yasuo
Y
Kano
Yuko
Y
Kurazono
Mizuyo
M
Matsuhisa
Eiji
E
Takata
Hiromi
H
Takata
Toshihiko
T
Atsumi
Kunio
K
Iwamatsu
Katsuyoshi
K
Shitara
Eiki
E
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D015780:Carbapenems / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D007093:Imidazoles / Q000737:chemistry; D007700:Kinetics; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry
D000900:Anti-Bacterial Agents; C524634:CP5484; D015780:Carbapenems; D007093:Imidazoles; D013844:Thiazoles