1,2-Diarylimidazoles as potent, cyclooxygenase-2 selective, and orally active antiinflammatory agents.
Series of 1,2-diarylimidazoles has been synthesized and found to contain highly potent and selective inhibitors of the human COX-2 enzyme. The paper describes a short synthesis of the target 1,2-diarylimidazoles starting with aryl nitriles. Different portions of the diarylimidazole (I) were modified to establish SAR. Systematic variations of the substituents in the aryl ring B have yielded very potent (IC50 = 10-100 nm) and selective (1000-12500) inhibitors of the COX-2 enzyme. The study on the influence of substituents in the imidazole ring established that a CF3 group at position 4 gives the optimum oral activity. A number of the diarylimidazoles showed excellent inhibition in the adjuvant induced arthritis model (e.g., ED50 = 0.02 mpk for 22 and 34). The diarylimidazoles are also potent inhibitors of carrageenan-induced edema (ED50 = 9-30 mpk) and hyperalgesia (ED50 = 11-40 mpk). Several orally active diarylimidazoles show no GI toxicity in the rat and mouse up to 200 mpk.
Khanna
I K
IK
Searle Research and Development, Skokie, Illinois 60077, USA.
Weier
R M
RM
Yu
Y
Y
Xu
X D
XD
Koszyk
F J
FJ
Collins
P W
PW
Koboldt
C M
CM
Veenhuizen
A W
AW
Perkins
W E
WE
Casler
J J
JJ
Masferrer
J L
JL
Zhang
Y Y
YY
Gregory
S A
SA
Seibert
K
K
Isakson
P C
PC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000138:chemical synthesis* / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007527:Isoenzymes; D008565:Membrane Proteins; D051379:Mice; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013450:Sulfones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000096926:Benzenesulfonamides
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D013449:Sulfonamides; D013450:Sulfones; C106271:2-(3-chlorophenyl)-4-trifluoromethyl-1-(4-methylsulfonylphenyl)imidazole; C106315:4-(2-(3-chlorophenyl)-4-trifluoromethylimidazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; C496512:Ptgs1 protein, mouse; C496513:Ptgs1 protein, rat