In Vivo Activities of Peptidic Prodrugs of Novel Aminomethyl Tetrahydrofuranyl-1β-Methylcarbapenems

Abstract

A series of novel aminomethyl tetrahydrofuranyl (THF)-1β-methylcarbapenems which have excellent broad-spectrum antibacterial activities exhibit modest efficacies against acute lethal infections (3.8 mg/kg of body weight against Escherichia coli and 0.9 mg/kg against Staphylococcus aureus) in mice when they are administered orally. In an effort to improve the efficacies of orally administered drugs through enhanced absorption by making use of a peptide-mediated transport system, several different amino acids were added at the aminomethyl THF side chains of the carbapenem molecules. The resulting peptidic prodrugs withl-amino acids demonstrated improved efficacy after oral administration, while the d forms were less active than the parent molecules. After oral administration increased (3 to 10 times) efficacy was exhibited with the alanine-, valine-, isoleucine-, and phenylalanine-substituted prodrugs against acute lethal infections in mice. Median effective doses (ED50s) of <1 mg/kg against infections caused by S. aureus, E. coli,Enterobacter cloacae, or penicillin-susceptibleStreptococcus pneumoniae were obtained after the administration of single oral doses. Several of the peptidic prodrugs were efficacious against Morganella morganii,Serratia marcescens, penicillin-resistant S. pneumoniae, extended-spectrum β-lactamase-producingKlebsiella pneumoniae, and E. coli infections, with ED50s of 1 to 14 mg/kg by oral administration compared with ED50s of 14 to >32 mg/kg for the parent molecules. In general, the parent molecules demonstrated greater efficacy than the prodrugs against these same infections when the drugs were administered by the subcutaneous route. The parent molecule was detectable in the sera of mice after oral administration of the peptidic prodrugs.

Structure and function of eukaryotic peptide transporters

“…This shows both that L-dopa-L-Phe is taken up more effectively by the peptide transporter than is the free L-dopa by amino acid transporter(s), and that the peptide is rapidly hydrolysed by intracellular peptidases. A similar approach was used to improve the oral bioavailability of a series of novel broad-spectrum antibacterials [aminomethyl tetrahydrofuranyl (THF)-1 imethylcarbapenems] [151]. These have a 3-to 10-fold higher efficacy after oral administration than the peptidyl prodrug (with the L-stereoisomer of Ala, Val, Ile or Phe added at the aminomethyl THF side chain of the active drug molecule).…”

Intestinal Absorption of Drugs Mediated by Drug Transporters: Mechanisms and Regulation

“…In addition, peptidic prodrugs of a novel aminomethyl tetrahydrofuranyl-1 b-methylcarbapenem (CL 191,121) with L-amino acids such as alanine, valine, isoleucine and phenylalanine have been shown to improve the e‹cacies after oral administration, though PEPT1-mediated transport was not directly demonstrated. 44) Another possible approach is to conjugate a dipeptide to parental drugs, thus producing peptidyl prodrugs. Ezra et al synthesized dipeptidyl-bisphosphonates, Pro-Phe-pamidronate and ProPhe-alendronate, and successfully demonstrated the improvement of oral absorption of these dipeptidylbisphosphonates.…”

The Biochemistry of Drug Metabolism — An Introduction. Part 3. Reactions of Hydrolysis and Their Enzymes

“…Its main biotransformation route is by amide hydrolysis to the corresponding carboxylic acid metabolite. The generic carbapenem antibiotics 3.103 are potential prodrugs [88]. The compound with a ÀCH 2 NH 2 side chain in position (2R) showed excellent in vitro antibacterial activity yet was poorly active in mice following oral administration.…”