3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) phenyl ketone as a potent and orally active cyclooxygenase-2 selective inhibitor: synthesis and biological evaluation.
Incorporation of a spacer group between the central scaffold and the aryl ring resulted in a new cyclooxygenase-2 (COX-2) selective inhibitor core structure, 3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) phenyl ketone (20), with COX-2 IC50 = 0.25 microM and COX-1 IC50 = 14 microM (human whole blood assay). Compound 20 was orally active in the rat air pouch model of inflammation, inhibiting white blood cell infiltration and COX-2-derived PG production. Our data support the identification of a novel COX-2 selective inhibitor core structure exemplified by 20.
Khanapure
Subhash P
SP
NitroMed, Inc., 125 Spring Street, Lexington, Massachusetts 02421, USA. skhanapure@nitromed.com
Augustyniak
Michael E
ME
Earl
Richard A
RA
Garvey
David S
DS
Letts
L Gordon
LG
Martino
Allison M
AM
Murty
Madhavi G
MG
Schwalb
David J
DJ
Shumway
Matthew J
MJ
Trocha
Andrzej M
AM
Young
Delano V
DV
Zemtseva
Irina S
IS
Janero
David R
DR
D000284:Administration, Oral; D000818:Animals; D002351:Carrageenan; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C501706:3-(4-(methylsulfonyl)phenyl)-5-(trifluoromethyl)(2-pyridyl) phenyl ketone; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D011725:Pyridines; D013450:Sulfones; D002351:Carrageenan; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone