Selective cyclooxygenase-2 inhibitors: heteroaryl modified 1,2-diarylimidazoles are potent, orally active antiinflammatory agents.
A series of heteroaryl modified 1,2-diarylimidazoles has been synthesized and found to be potent and highly selective (1000-9000-fold) inhibitors of the human COX-2. 3-Pyridyl derived COX-2 selective inhibitor (25) exhibited excellent activity in acute (carrageenan induced paw edema, ED(50) = 5.4 mg/kg) and chronic (adjuvant induced arthritis, ED(50) = 0.25 mg/kg) models of inflammation. The relatively long half-life of 25 in rat and dog prompted investigation of the pyridyl and other heteroaromatic systems containing potential metabolic functionalities. A number of substituted pyridyl and thiazole containing compounds (e.g., 44, 46, 54, 76, and 78) demonstrated excellent oral activity in every efficacy model evaluated. Several orally active diarylimidazoles exhibited desirable pharmacokinetics profiles and showed no GI toxicity in the rat up to 100 mg/kg in both acute and chronic models. The paper describes facile and practical syntheses of the targeted diarylimidazoles. The structure-activity relationships and antiinflammatory properties of a series of diarylimidazoles are discussed.
Khanna
I K
IK
Discovery Medicinal Chemistry and Inflammatory Disease Research, Pharmacia Corporation, 4901 Searle Parkway, Skokie, Illinois 60077, USA. ish.k.khanna@monsanto.com
Yu
Y
Y
Huff
R M
RM
Weier
R M
RM
Xu
X
X
Koszyk
F J
FJ
Collins
P W
PW
Cogburn
J N
JN
Isakson
P C
PC
Koboldt
C M
CM
Masferrer
J L
JL
Perkins
W E
WE
Seibert
K
K
Veenhuizen
A W
AW
Yuan
J
J
Yang
D C
DC
Zhang
Y Y
YY
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001169:Arthritis, Experimental / Q000188:drug therapy; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004285:Dogs; D004487:Edema / Q000188:drug therapy; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D009570:Nitriles / Q000138:chemical synthesis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry; D051381:Rats; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D008565:Membrane Proteins; D009570:Nitriles; D011725:Pyridines; D013449:Sulfonamides; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases