(E)-[2-(4-Methylsulphonylphenyl)-1-cyclopentenyl-1-methyliden](arylmethyloxy)amines. Methyleneaminoxymethyl (MAOM) analogues of diarylcyclopentenyl cyclooxygenase-2 inhibitors: synthesis and biological properties.
The (E)-[2-(4-Methylsulphonylphenyl)-1-cyclopentenyl-1-methyliden](methyloxy)amine (5) and (arylmethyloxy)amines (6-12) were designed in order to verify the effects on the biological properties of the substitution of an aryl of selective diarylcyclopentenyl cyclooxygenase-2 (COX-2) inhibitors of type 3 with a methyleneaminoxymethyl moiety (MAOMM). Compounds 5-12 were tested in vitro for their inhibitory activity towards COX-1 and COX-2 by measuring prostaglandin E2 (PGE2) production in U937 cell lines and activated J774.2 macrophages, respectively. The compound with the highest in vitro activity towards COX-2 (9) was also assayed in vivo for its antiinflammatory activity by means of the carrageenan-induced paw edema test in rats. Some of the new compounds showed an appreciable in vitro COX-2 inhibitory activity, with IC(50) values in the microM (6,7,9,10,11) range. Compound 9 also exhibited an appreciable in vivo activity (29% inhibition at a dose of 30 mg kg(-1)) when administered intraperitoneally. The structural parameters of 9 were determined by X-ray crystallographic analysis.
Balsamo
Aldo
A
Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 6, Italy. balsamo@farm.unipi.it
Coletta
Isabella
I
Domiano
Paolo
P
Guglielmotti
Angelo
A
Landolfi
Carla
C
Mancini
Francesca
F
Milanese
Claudio
C
Orlandini
Elisabetta
E
Rapposelli
Simona
S
Pinza
Mario
M
Macchia
Bruno
B
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D002351:Carrageenan; D002460:Cell Line; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
C470126:(2-(4-methylsulphonylphenyl)-1-cyclopentenyl-1-methyliden)(methyloxy)amine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D003517:Cyclopentanes; D006574:Heterocyclic Compounds, 2-Ring; D007527:Isoenzymes; D008565:Membrane Proteins; D013438:Sulfhydryl Compounds; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat