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 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.