title: 1,3-Diaryl-4,5,6,7-tetrahydro-2H-isoindole derivatives: a new series of potent and selective COX-2 inhibitors in which a sulfonyl group is not a structural requisite.
abstract: Novel tetrahydro-2H-isoindoles have been prepared and evaluated as inhibitors of the COX-2 isoenzyme. A 1,3-diaryl substitution on the central polycyclic ring system and absence of a sulfonyl moiety are the two structural features of this chemical series. A short and easy synthetic pathway produced several derivatives which were shown to be potent and selective COX-2 vs COX-1 inhibitors (IC(50) = 0. 6-100 nM for COX-2, 100->1000 nM for COX-1). Structural modifications established that a bicyclic ring appended to the pyrrole nucleus and 4,4'-difluoro substitution on the phenyl rings were optimal for high inhibitory potency. Activity was confirmed in the human whole blood assay and subsequently in the murine air-pouch model in which in vivo PGE2 inhibitory activity was evaluated with respect to gastric tolerance (ED(50) for inhibition of exudate PGE2 of 3 mg/kg and gastric PGE2 of 20 mg/kg). Gastric tolerance was further assessed after administration to mice of high doses (up to 400 mg/kg) of the inhibitors by measurement of gastric damage. This panel of studies allowed selection of a number of tetrahydro-2H-isoindoles which were compared in the adjuvant-induced arthritis model. Compounds 32 and 37 showed the most potent activity with ED(50) values for edema inhibition in the noninjected paw of 0. 35 and 0.15 mg/kg/day, respectively, after oral administration. In addition, this interesting antiinflammatory profile was accompanied by a protective effect against arthritis-induced osteopenia, the decrease being 50% with a dose of 0.25 mg/kg/day.
authors: Division D of Medicinal Chemistry and Division of Rhumatology, Institut de Recherche Servier, 11 rue des Moulineaux, 92150 Suresnes, France.
authors: B
authors: B
authors: Portevin
authors: C
authors: C
authors: Tordjman
authors: P
authors: P
authors: Pastoureau
authors: J
authors: J
authors: Bonnet
authors: De Nanteuil G
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001169:Arthritis, Experimental / Q000188:drug therapy; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D017737:Macrophages, Peritoneal / Q000201:enzymology; D008565:Membrane Proteins; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: C433232:3,5-bis(4-fluorophenyl)-4--azatricyclo(5.2.2.0(2,6))undeca-2,5-diene; C433231:3,5-bis(4-fluorophenyl)-4-azatricyclo(5.2.1.0(2,6))deca-2,5-diene; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D007527:Isoenzymes; D008565:Membrane Proteins; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse