Aryl-substituted methyleneaminoxymethyl (MAOM) analogues of diarylcyclopentenyl cyclooxygenase-2 inhibitors: effects of some structural modifications on their biological properties.
The (E)-[2-(4-aminosulfonylphenyl)-1-cyclopentenyl-1-methyliden]-(arylmethyloxy)amines (6a,b), which are the sulfonamidic analogues of the previously described methylsulfonyl derivatives 5a,b, and their corresponding sulfides (7a,b) and sulfoxides (8a,b) were synthesised in order to obtain information about the role played by these different sulphur-containing groups in the cyclooxygenase-2 inhibitory activity of this class of compounds. In addition, other chemical manipulations concerning the oxime-ether substituent of this type of derivatives were affected by preparing compounds 9a,b, which present a methyl group on the oximic carbon of the oxime-ether chain of 5a,b, and compounds 10 and 11, in which the atomic sequence (C=NOCH(2)) of the MAOMM of 8b and 5b, respectively, is inverted. Compounds 6-11 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. Some of the new compounds showed an appreciable in vitro COX-2 inhibitory activity, with IC(50) values in the microM (7a,b, 8a and 9b) or sub-microM (8b) range. This last compound was also assayed in vivo for its antiinflammatory activity by means of the carrageenan-induced paw edema test in rats. No inhibitory effects were detected up to dose of 30 mg kg(-1) orally administered.
Dipartimento di Scienze Farmaceutiche, Facoltà di Farmacia, Università di Pisa, via Bonanno 6, 56126, Pisa, Italy. balsamo@farm.unipi.it
Aldo
A
Balsamo
Isabella
I
Coletta
Angelo
A
Guglielmotti
Carla
C
Landolfi
Annalina
A
Lapucci
Francesca
F
Mancini
Claudio
C
Milanese
Filippo
F
Minutolo
Elisabetta
E
Orlandini
Gabriella
G
Ortore
Mario
M
Pinza
Simona
S
Rapposelli
D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D003517:Cyclopentanes / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D004487:Edema / Q000188:drug therapy; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases; D051381:Rats; D013329:Structure-Activity Relationship; D020298:U937 Cells
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D003517:Cyclopentanes; D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone