GREENE ML, BARBACHYN MR, JACOBSEN SK, CHEN JJ, LU CV, PERRAULT WR, FORD CW, HAMEL JC, MORIN SE, ZURENKO GE; Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd : 2002 : San Diego, Calif.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2002 Sep 27-30; 42: abstract no. F-1333.
Pharmacia, Kalamazoo, MI
The oxazolidinone class of antibacterials, exemplified by linezolid (marketed as Zyvox[TM]), has emerged as an important treatment option for multi-drug resistant and sensitive gram-positive infections. Due to the sucess of linezolid, extensive structure activity relationships (SAR) have been conducted at Pharmacia. Early studies in the piperazinyl phenyl series (eperezolid analogs) showed a fluorine appendage on the phenyl B-ring could improve antibacterial potency. Additionally, SAR studies demonstrated the thiomorpholine ring was a suitable replacement for the morpholine ring, as shown by PNU-100480 with an MIC of 4 microg/mL against S. aureus UC9213. Building on these two ideas, we decided to synthesize the thiomorpholinyl difluorophenyl analogs, which we believed would have improved antibacterial activity. Indeed, many of the analogs synthesized in this series had potent in vitro and in vivo activity. PNU-288034 showed a consistent improvement in in vitro potency when compared with linezolid (MIC[90] of 2 microg/mL vs. MIC[90] of 4 microg/mL for S. aureus, respectively), and comparable in vivo efficacy. Based on these preliminary results and other findings, PNU-288034 was selected for further preclinical development. [figure: see text] The synthesis and antibacterial activity of PNU-288034 as well as other analogs in the thiomorpholinyl difluorophenyl series will be presented.
Publication Types:
Keywords:
- Acetamides
- Anti-Bacterial Agents
- In Vitro
- Microbial Sensitivity Tests
- Oxazoles
- Oxazolidinones
- Phenylurea Compounds
- Structure-Activity Relationship
- U 100592
- linezolid
- pyriminil
Other ID:
UI: 102267769
From Meeting Abstracts