Synthesis and structure-activity relationships of novel parenteral carbapenems, CS-023 (R-115685) and related compounds containing an amidine moiety.
In order to design a new parenteral 1beta-methylcarbapenem antibiotic which has a broad antibacterial spectrum and improved plasma half-life, a series of 1beta-methylcarbapenems with 5-substituted pyrrolidine-3-ylthio groups including an amidine moiety at the C-2 position have been synthesized and structure-activity relationships were investigated. Among those carbapenem derivatives, CS-023 (R-115685) showed a broad spectrum and excellent antibacterial activity against Gram-positive and Gram-negative bacteria. This compound also showed sufficient dehydropeptidase-I (DHP-I) stability and high urinary recovery in animals after subcutaneous administration without cilastatin, a DHP-I inhibitor. Based on these characteristics, CS-023 was selected for further study.
Kawamoto
Isao
I
Research Laboratories, Sankyo Co., Ltd. 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Shimoji
Yasuo
Y
Kanno
Osamu
O
Kojima
Katsuhiko
K
Ishikawa
Katsuya
K
Matsuyama
Emi
E
Ashida
Yuka
Y
Shibayama
Takahiro
T
Fukuoka
Takashi
T
Ohya
Satoshi
S
D000818:Animals; D015780:Carbapenems / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
D015780:Carbapenems