6-(substituted methylene)penems, potent broad spectrum inhibitors of bacterial beta-lactamase. IV. Kidney stability, serum binding and additional biological evaluation of racemic derivatives.
Sodium (5RS)-Z-6-(substituted methylene)penem-3-carboxylates (3) are extremely potent inhibitors of bacterial beta-lactamases, but some members of this group of compounds are highly bound to human serum, while others are readily degraded by renal dehydropeptidase I enzyme. Consequently, the stability of a variety of 6-(substituted methylene)penems (3) to human kidney homogenate, their binding to human serum and their activity in a mouse infection model was investigated at an early stage, and were instrumental in the selection of the 1,2,3-triazolylmethylene derivatives (e.g. 3k) as a class of compounds worthy of further evaluation.
Bennett
I S
IS
SmithKline Beecham Pharmaceuticals, Chemotherapeutic Research Centre, Surrey, UK.
Broom
N J
NJ
Coleman
K
K
Coulton
S
S
Edwards
P D
PD
Francois
I
I
Griffin
D R
DR
Osborne
N F
NF
Woodall
P M
PM
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D001798:Blood Proteins / Q000378:metabolism*; D004355:Drug Stability; D004927:Escherichia coli Infections / Q000188:drug therapy; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D011485:Protein Binding; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams
D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams