Orally active carbapenem antibiotics I. Antibacterial and pharmacokinetic potential of 2-phenyl and 2-thienylcarbapenems.
In order to design orally active carbapenem antibiotics effective against beta-lactam-resistant pathogens, such as penicillin-resistant Streptococcus pneumoniae (PRSP) and beta-lactamase non-producing ampicillin-resistant Haemophilus influenzae (BLNAR), a series of novel 2-phenylcarbapenems and some 2-thienyl derivatives were synthesized and tested for antibacterial activities. These compounds were highly active against PRSP, BLNAR, and major Gram-positive and Gram-negative bacteria that cause community-acquired infections. Their pivaloyloxymethylester-type prodrug exhibited good oral absorption in mice, suggesting that this series of carbapenems were promising as a prototype of novel orally active beta-lactams.
Sunagawa
Makoto
M
Sumitomo Pharmaceuticals Research Division, 1-98, Kasugade Naka 3-Chome, Konohana-ku, Osaka 554-0022, Japan. makoto-sunagawa@ds-pharma.co.jp
Ueda
Yutaka
Y
Okada
Shin-Ichiro
S
Watanabe
Shoji
S
Hashizuka
Takahiko
T
Hori
Seiji
S
Sasaki
Akira
A
Eriguchi
Yoshiro
Y
Kanazawa
Katsunori
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D015780:Carbapenems / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004150:Dipeptidases / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007202:Indicators and Reagents; D007408:Intestinal Absorption; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D007202:Indicators and Reagents; D013876:Thiophenes; D004150:Dipeptidases; C038937:dipeptidase