Studies on penem and carbapenem. I. Syntheses and oral absorption of ester-type prodrugs of sodium (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3-c arboxylat e.
Acyloxyalkyl esters (2a-d), alkyloxycarbonyloxyalkyl esters (2e-g) and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester (2h) of (5R,6S)-2-(2-fluoroethylthio)-6-[(1R)-1-hydroxyethyl]penem-3- carboxylic acid (1) were synthesized. Enhanced oral absorption was observed in mice reflecting increased lipophilicity, compared with the parent 1 itself. Among them, the ester 2h showed a prolonged plasma level and a large area under the blood concentration-time curve (AUC) in rats. These ester-type prodrugs of penem 1 in phosphate buffer (pH 6.86) were much more stable than those of cephalosporins which easily degraded via isomerization to delta 2 cephalosporins.
Miyauchi
M
M
Sankyo Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
Endo
R
R
Watanabe
K
K
Kawahara
Y
Y
Iwata
M
M
Kawamoto
I
I
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004952:Esters; D007769:Lactams; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains
D000900:Anti-Bacterial Agents; D004952:Esters; D007769:Lactams; D011355:Prodrugs; C051057:2-(2-fluoroethylthio)-6-(1-hydroxyethyl)penem-3-carboxylate