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 1β-methylcarbapenem antibiotic which has a broad antibacterial spectrum and improved plasma half-life, a series of 1β-methylcarbapenems with 5-substituted pyrrolidine-3-ylthio groups including an amidine moiety at the C-2 position have been synthesized and structu...

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Published in:Journal of antibiotics 2003/06/25, Vol.56(6), pp.565-579
Main Authors: KAWAMOTO, ISAO, SHIMOJI, YASUO, KANNO, OSAMU, KOJIMA, KATSUHIKO, ISHIKAWA, KATSUYA, MATSUYAMA, EMI, ASHIDA, YUKA, SHIBAYAMA, TAKAHIRO, FUKUOKA, TAKASHI, OHYA, SATOSHI
Format: Article
Language:English
Subjects:
Animals
Antibacterial agents
Antibiotics. Antiinfectious agents. Antiparasitic agents
Biological and medical sciences
Carbapenems - chemical synthesis
Carbapenems - chemistry
Carbapenems - pharmacology
Humans
Medical sciences
Mice
Microbial Sensitivity Tests
Pharmacology. Drug treatments
Structure-Activity Relationship
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Summary:In order to design a new parenteral 1β-methylcarbapenem antibiotic which has a broad antibacterial spectrum and improved plasma half-life, a series of 1β-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-1 (DHP-1) 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.
ISSN:0021-8820
1881-1469
DOI:10.7164/antibiotics.56.565