Session: Novel b-Lactams and b-Lactamase Inhibitors
Location:
Exhibit Hall
Session Date:
Sunday, 9/26/99
Session Time:
1:30 pm - 3:00 pm
Design, Synthesis and In vitro Antibacterial Properties of Novel
3-Heteroarylthio Cephems with Anti-MRSA Activity; Amino Acid Prodrug
Approach to Solubility Improvement
T. Glinka, R. Frith, S. Halas, G. Nudelman, C. Whitehead, A. Cho, J. Crawford,
M. Ludwikow, T. Calkins, S. Chamberland, M. Price, S. Hecker, V. Lee
Microcide Pharmaceuticals Inc.: Mountain View, CA
The desirable antibacterial properties of cephalosporin MC-02,479 (RWJ-54428)
(Glinka, et al., 37th ICAAC #167, 1997) discovered recently at Microcide can be
attributed to the cephem 3-(pyrid-4-ylthio) substituent as well as the
aminoethylthiomethyl appendage attached to the pyridine ring. The pyridine substituent
also provides a protonation site which, at acidic pH, allows solubility sufficient for
intravenous administration. We have further explored related 3-heteroarylthio cephems in
which the aminoethylthio subsituent is attached to a variety of other heterocycles. As a
result, we have identified a wide range of novel analogs of MC-02,479 with high
antibacterial activity against b-lactam resistant Gram-positive organisms, including
MRSA. The pH-solubility profiles of these novel analogs do not achieve desired
solubility levels at acceptable pH. A prodrug approach, employing a cleavable alanyl
derivative of the aminothiazole moiety, was used to improve the solubility of MC-03,791.
In vivo evaluation of its prodrug MC-03,971 showed excellent bioavailability of the
parent cephalosporin. |
