GORDEEV MF, LUEHR GW, GADWOOD RC, SCOTT CR, HACKBARTH CJ, LOPEZ S, TRIAS J, FRIIS JM, WILLIAMS MG, HOSLEY JD, COURTNEY M, ADAMS WJ, PATEL DV; Interscience Conference on Antimicrobial Agents and Chemotherapy (41st : 2001 : Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2001 Dec 16-19; 41: abstract no. F-1047.
Versicor Inc., Fremont, CA
Oxazolidinones are a new class of protein synthesis inhibitors active against a wide range of clinically relevant gram-positive bacteria. In the course of our work toward second generation oxazolidinones with improved potency and spectrum, a novel series of 3-(4-amido)phenyl oxazolidinones bearing a 5-(S)-thioamidomethyl substituent (C-5 group) were synthesized and evaluated for activity against RTI-pathogens. Within this series, a replacement of the amide C-5 group for a thioamide resulted in a significant improvement of antibacterial activity and spectrum. Thus, the compound VRC-3782 is active against S. aureus (VSAU1009), E. faecium (VEFA1005), S. pneumoniae (VSPN1006) and H. influenzae (VHIN1009) with MIC values of 1, 1, 0.25, and 4 microg/mL, respectively. S. aureus MIC90 values for these compounds (2 and 1 microg/mL, respectively) are 2-4-fold better than that for linezolid (4 microg/mL). Compounds VRC-3783 and VRC-4104 are orally bioavailable and essentially equipotent to linezolid in a S. aureus Smith mouse septicemia model. [figure: see text] Single dose pharmacokinetic data for these leads in the male Sprague-Dawley rat are presented. The oral bioavailability of the compound VRC-3783 ranged from 75-99%, with Cmax values of up to 24 microg/mL.
Publication Types:
Keywords:
- Acetamides
- Animals
- Anti-Bacterial Agents
- Gram-Positive Bacteria
- Haemophilus influenzae
- Male
- Mice
- Microbial Sensitivity Tests
- Muridae
- Oxazolidinones
- Rats
- Rats, Sprague-Dawley
- Thioamides
- linezolid
- pharmacokinetics
Other ID:
UI: 102270027
From Meeting Abstracts