Selective inducible microsomal prostaglandin E(2) synthase-1 (mPGES-1) inhibitors derived from an oxicam template.
Here we describe the SAR of a series of potent and selective mPGES-1 inhibitors based on an oxicam template. Compound 13j demonstrated low nanomolar mPGES-1 inhibition in an enzyme assay. In addition, it displayed PGE(2) inhibition in a cell-based assay (0.42microM) and had over 238-fold selectivity for mPGES-1 over COX-2 and over 200-fold selectivity for mPGES-1 over 6-keto PGF(1alpha).
Wang
Jane
J
Pfizer Inc. St. Louis Laboratory, PGRD Research, 700 Chesterfield PKWY W, Chesterfield, MO 63017, USA. jl47wang@yahoo.com
Limburg
David
D
Carter
Jeff
J
Mbalaviele
Gabriel
G
Gierse
James
J
Vazquez
Michael
M
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; D013843:Thiazines; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases