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:

• Meeting Abstracts

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:

• GWAIDS0030390

UI: 102270027

From Meeting Abstracts