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

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...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2000-11, Vol.43 (24), p.4582-4593
Main Authors: Portevin, Bernard, Tordjman, Charles, Pastoureau, Philippe, Bonnet, Jacqueline, De Nanteuil, Guillaume
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal - chemistry
Anti-Inflammatory Agents, Non-Steroidal - pharmacology
Anti-Inflammatory Agents, Non-Steroidal - toxicity
Arthritis, Experimental - drug therapy
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Cyclooxygenase 1
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors - chemical synthesis
Cyclooxygenase Inhibitors - chemistry
Cyclooxygenase Inhibitors - pharmacology
Cyclooxygenase Inhibitors - toxicity
Heterocyclic Compounds, 3-Ring - chemical synthesis
Heterocyclic Compounds, 3-Ring - chemistry
Heterocyclic Compounds, 3-Ring - pharmacology
Heterocyclic Compounds, 3-Ring - toxicity
Humans
In Vitro Techniques
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Indoles - toxicity
Isoenzymes - antagonists & inhibitors
Macrophages, Peritoneal - enzymology
Medical sciences
Membrane Proteins
Mice
Pharmacology. Drug treatments
Prostaglandin-Endoperoxide Synthases
Stomach - drug effects
Stomach - pathology
Structure-Activity Relationship
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 (IC50 = 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 (ED50 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 ED50 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm990965x