title: Prodrugs of cephalosporin RWJ-333441 (MC-04,546) with improved aqueous solubility.
abstract: 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.
authors.affiliation: Microcide Pharmaceuticals, Inc., Mountain View, California, USA. scottjhecker@attbi.com
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hecker
authors.forename: Trevor
authors.initials: T
authors.lastname: Calkins
authors.forename: Mary E
authors.initials: ME
authors.lastname: Price
authors.forename: Keith
authors.initials: K
authors.lastname: Huie
authors.forename: Sharon
authors.initials: S
authors.lastname: Chen
authors.forename: Tomasz W
authors.initials: TW
authors.lastname: Glinka
authors.forename: Michael N
authors.initials: MN
authors.lastname: Dudley
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D007769:Lactams; D011355:Prodrugs; C452865:RWJ-333441; D014867:Water