title: Synthesis and COX-2 inhibitory properties of N-phenyl- and N-benzyl-substituted amides of 2-(4-methylsulfonylphenyl)cyclopent-1-ene-1-carboxylic acid and of their pyrazole, thiophene and isoxazole analogs.
abstract: Some N-phenyl- (7a-10a) and N-benzyl-substituted (7b-10b) amido analogs of cyclooxygenase (COX-2) selective tricyclic non-steroidal anti-inflammatory drugs have been synthesized with the aim to obtain information on the structural requirements for the COX-inhibitory activity. Compounds 7-10 were tested in vitro for their inhibitory properties only towards COX-2 enzyme by measuring prostaglandin E2 (PGE2) production on activated J774.2 macrophages. Some of the new compounds (7a, 8a, 9a and 9b) showed a modest activity, with percentage inhibition values near 30% at a concentration of 10 microM. These data have been tentatively explained by a conformational study which indicates that at least the N-phenyl-substituted amides 7a-9a present steric hindrances which may prevent a good interaction with COX-2 active site.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Facoltà di Farmacia, Università di Pisa, Via Bonanno, 6, 56100, Pisa, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
authors.forename: Annalina
authors.initials: A
authors.lastname: Lapucci
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orlandini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ortore
authors.forename: Mario
authors.initials: M
authors.lastname: Pinza
authors.forename: Aldo
authors.initials: A
authors.lastname: Balsamo
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins; D008968:Molecular Conformation; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007555:Isoxazoles; D008565:Membrane Proteins; D011720:Pyrazoles; D013876:Thiophenes; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone