THF carbapenems. Wyeth Ayerst

CL-191121 is one of three new tetrahydrofuranyl (THF) carbapenems, which possess stability to renal dihydropeptidase and beta-lactamases [162484], [387167], [418244] and have minimal binding to penicillin-binding proteins (PBPs) [163188]. Of the series of THF carbapenems, CL-191121 had the best activity against gram-positive organisms, particularly against Enterococcus faecalis. It demonstrated moderate oral activity against an Escherichia coli Infection in mice and was 20-fold more efficacious than imipenem [253186]. As the effective oral dose (ED50) was 11- to 14-fold higher than the effective subcutaneous dose, a series of bis-double ester prodrugs (of the aminomethyl-THF 1beta-methyl-carbapenems) was prepared, which showed substantially improved oral bioavailability in the mouse model (EU50 = 0.42 microg/ml following a single oral dose obtained for the most potent compound) [258726]. OCA-983 is a prodrug derivative of CL-191121 sharing potent inhibitory activity against class A and class C beta-lactamases [324244], although development of this compound is no longer being pursued.