Antibacterial oxazolidinones possessing a novel C-5 side chain. (5R)-trans-3-[3-Fluoro-4- (1-oxotetrahydrothiopyran-4-yl)phenyl]-2- oxooxazolidine-5-carboxylic acid amide (PF-00422602), a new lead compound.
Oxazolidinones possessing a C-5 carboxamide functionality (reverse amides) represent a new series of compounds that block bacterial protein synthesis. These reverse amides also exhibited less potency against monoamine oxidase (MAO) enzymes and thus possess less potential for the side effects associated with MAO inhibition. The title compound (14) showed reduced in vivo myelotoxicity compared to linezolid in a 14-day safety study in rats, potent in vivo efficacy in murine systemic infection models, and excellent pharmacokinetic properties.
Poel
Toni-Jo
TJ
Michigan Laboratories, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
Thomas
Richard C
RC
Adams
Wade J
WJ
Aristoff
Paul A
PA
Barbachyn
Michael R
MR
Boyer
Frederick E
FE
Brieland
Joan
J
Brideau
Roger
R
Brodfuehrer
Joanne
J
Brown
Alan P
AP
Choy
Allison L
AL
Dermyer
Michael
M
Dority
Michael
M
Ford
Charles W
CW
Gadwood
Robert C
RC
Hanna
Debra
D
Hongliang
Cai
C
Huband
Michael D
MD
Huber
Christopher
C
Kelly
Rose
R
Kim
Ji-Young
JY
Martin
Joseph P
JP
Pagano
Paul J
PJ
Ross
Daniel
D
Skerlos
Laura
L
Sulavik
Mark C
MC
Zhu
Tong
T
Zurenko
Gary E
GE
Prasad
J V N Vara
JV
D000081:Acetamides / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001682:Biological Availability; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D004285:Dogs; D024881:Drug Resistance, Bacterial; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D007275:Injections, Intravenous; D000069349:Linezolid; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus; D013290:Streptococcal Infections / Q000188:drug therapy; D013297:Streptococcus pyogenes; D013329:Structure-Activity Relationship
D000081:Acetamides; D000900:Anti-Bacterial Agents; D003499:Cyclic S-Oxides; D008996:Monoamine Oxidase Inhibitors; D023303:Oxazolidinones; C526807:PF 00422602; D000069349:Linezolid