Synthesis and biological activity of the penem antibiotic MEN 10700 and its orally absorbed ester MEN 11505.
The synthesis and biological properties of the new penem antibiotic MEN 10700 (6) and of its selected oral prodrug MEN 11505 (8f) are described. MEN 10700 showed a broad spectrum of activity, with high potency both on Gram-positive and Gram-negative strains. It also exhibited good antibacterial activity toward anaerobes and on strains selected for their resistance to other antibacterial agents (cefotaxime- or ceftazidime-resistant Gram-negative strains, ciprofloxacin-resistant E. coli, extended spectrum beta-lactamase producing and cephalosporinase inducible enterobacteria). MEN 10700 showed a very high stability to enzymatic degradation by renal dehydropeptidase DHP-I. After oral administration in rats of the pivaloyloxymethyl ester prodrug MEN 11505, the relative bioavailability of MEN 10700 was calculated as F=43%.
Arcamone
F M
FM
CNR-ICOCEA, Bologna, Italy.
Altamura
M
M
Perrotta
E
E
Crea
A
A
Manzini
S
S
Poma
D
D
Salimbeni
A
A
Triolo
A
A
Maggi
C A
CA
D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001682:Biological Availability; D015780:Carbapenems / Q000493:pharmacokinetics / Q000494:pharmacology; D004150:Dipeptidases / Q000378:metabolism; D007769:Lactams; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods; D010406:Penicillins / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D007769:Lactams; C418196:MEN 11505; C106870:Men 10700; D010406:Penicillins; D011355:Prodrugs; C040033:ritipenem; D004150:Dipeptidases; C038937:dipeptidase