Studies on anti-MRSA parenteral cephalosporins. IV. A novel water-soluble N-phosphono type prodrug for parental administration.
A systematic approach for improving the water-solubility of anti-MRSA (methicillin-resistant Staphylococcus aureus) cephalosporin derivatives is described. We first tried to improve the water-solubility of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-fluoromethoxyiminoacetamido]-3-[(E)-2-(1-methylimidazo[1,2-b]pyridazinium-6-yl)thiovinyl]-3-cephem-4-carboxylate (1a) by substitution of the C-3' pharmacophore. Replacement of the C-3' pharmacophore with a 1-methyl-4-pyridinio group improved the water-solubility without decreasing the anti-MRSA activity. Furthermore, we applied the N-modified prodrug strategy to the C-7 acyl group in order to enhance the water-solubility drastically. Among the compounds prepared, the N-phosphono type prodrugs 2a(1-methylimidazo[1,2-b]pyridazinium derivative) and 2b (1-methyl-4-pyridinio derivative) showed water-solubility appropriate for a product intended for intravenous injection and in vivo anti-MRSA activity comparable to that of vancomycin.
Ishikawa
T
T
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd, Osaka, Japan.
Nakayama
Y
Y
Tomimoto
M
M
Niwa
S I
SI
Kamiyama
K
K
Hashiguchi
S
S
Iizawa
Y
Y
Okonogi
K
K
Miyake
A
A
D000818:Animals; D001426:Bacterial Proteins; D002352:Carrier Proteins; D002511:Cephalosporins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006602:Hexosyltransferases / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007267:Injections; D008297:Male; D016106:Methicillin Resistance / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009097:Multienzyme Complexes / Q000378:metabolism; D002267:Muramoylpentapeptide Carboxypeptidase; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D012995:Solubility; D013055:Spectrophotometry, Infrared; D013211:Staphylococcus aureus / Q000187:drug effects*
D001426:Bacterial Proteins; D002352:Carrier Proteins; D002511:Cephalosporins; D009097:Multienzyme Complexes; D046915:Penicillin-Binding Proteins; D011355:Prodrugs; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase