Prodrugs of cephalosporin RWJ-333441 (MC-04,546) with improved aqueous solubility.
To improve the aqueous solubility of anti-methicillin-resistant Staphylococcus aureus cephalosporin RWJ-333441 for parenteral administration, acyl derivatives of the C-3 primary amino group were prepared and evaluated for solubility, cleavage in serum in vitro, and conversion to RWJ-333441 in vivo. Improved solubility at physiologic pH values and release of RWJ-333441 in vitro and in vivo were observed for several prodrugs, including the aspartate derivative RWJ-333442.
Hecker
Scott J
SJ
Microcide Pharmaceuticals, Inc., Mountain View, California, USA. scottjhecker@attbi.com
Calkins
Trevor
T
Price
Mary E
ME
Huie
Keith
K
Chen
Sharon
S
Glinka
Tomasz W
TW
Dudley
Michael N
MN
D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002511:Cephalosporins / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D007769:Lactams; D008253:Macaca mulatta; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D012995:Solubility; D014867:Water / Q000737:chemistry
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D007769:Lactams; D011355:Prodrugs; C452865:RWJ-333441; D014867:Water