Synthesis and structure-activity relationship of a new series of COX-2 selective inhibitors: 1,5-diarylimidazoles.
The synthesis and the pharmacological activity of a series of 1,5-diarylimidazoles developed as potent and selective cyclooxygenase-2 (COX-2) inhibitors are described. The new compounds were evaluated both in vitro (COX-1 and COX-2 inhibition in human whole blood) and in vivo (carrageenan-induced paw edema, air-pouch, and hyperalgesia tests). Modification of all the positions of two regioisomeric imidazole cores led to the identification of 4-[4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl]benzenesulfonamide (UR-8880, 51f) as the best candidate, which is now undergoing Phase I clinical trials.
Almansa
Carmen
C
Research Center, Grupo Uriach, Av. Camí Reial 51-57, E-08184 Palau-Solità i Plegamans, Spain. chem-almansa@uriach.com
Alfón
José
J
de Arriba
Alberto F
AF
Cavalcanti
Fernando L
FL
Escamilla
Ignasi
I
Gómez
Luis A
LA
Miralles
Agustí
A
Soliva
Robert
R
Bartrolí
Javier
J
Carceller
Elena
E
Merlos
Manuel
M
García-Rafanell
Julián
J
D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001665:Binding Sites; D002460:Cell Line; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008565:Membrane Proteins; D008958:Models, Molecular; D010147:Pain Measurement; D010437:Peptic Ulcer / Q000139:chemically induced; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone; D007093:Imidazoles; D007527:Isoenzymes; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D013449:Sulfonamides; C476594:4-(4-chloro-5-(3-fluoro-4-methoxyphenyl)imidazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C496540:PTGS2 protein, human