Synthesis of Celecoxib Analogues Possessing a N-Difluoromethyl-1,2-dihydropyrid-2-one 5-Lipoxygenase Pharmacophore: Biological Evaluation as Dual Inhibitors of Cyclooxygenases and 5-Lipoxygenase with Anti-Inflammatory Activity

• Published in: Journal of medicinal chemistry Vol. 52; no. 6; pp. 1525 - 1529
• Main Authors: Chowdhury, Morshed A, Abdellatif, Khaled R. A, Dong, Ying, Das, Dipankar, Suresh, Mavanur R, Knaus, Edward E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.03.2009; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Celecoxib; Chemistry, Medicinal; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - pharmacology; Drug Evaluation, Preclinical; Humans; Life Sciences & Biomedicine; Lipoxygenase Inhibitors - chemical synthesis; Lipoxygenase Inhibitors - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrazoles - chemical synthesis; Pyrazoles - pharmacology; Science & Technology; Spectrophotometry, Infrared; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; AGENTS; COX-2 INHIBITORS; DERIVATIVES; DRUGS; Prostaglandin-endoperoxide synthase; Rat; Sulfone; Cyclooxygenase 2; Cyclooxygenase 2 inhibitor; Selectivity; Modeling; Pyridine derivatives; Arachidonate 5-lipoxygenase; Pyrazole derivatives; Chemical synthesis; Pyridone derivatives; Sulfonamide; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Celecoxib; In vitro; Biological activity; Non steroidal antiinflammatory agent; In vivo; Vertebrata; Mammalia; Animal; Oxidoreductases; Fluorine Organic compounds
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm8015188

A novel class of 1-(4-methanesulfonylphenyl and 4-aminosulfonylphenyl)-5-[4-(1-difluoromethyl-1,2-dihydropyrid-2-one)]-3-trifluoromethyl-1H-pyrazole hybrid cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LOX) inhibitory anti-inflammatory agents was designed. Replacement of the tolyl ring present in celecoxib by the N-difluoromethyl-1,2-dihydropyrid-2-one moiety provided compounds showing dual selective COX-2/5-LOX inhibitory activities. 1-(4-Aminosulfonylphenyl)-5-[4-(1-difluoromethyl-1,2-dihydropyrid-2-one)]-3-trifluoromethyl-1H-pyrazole exhibited good anti-inflammatory (AI) activity (ED50 = 27.7 mg/kg po) that compares favorably with the reference drugs celecoxib (ED50 = 10.8 mg/kg po) and ibuprofen (ED50 = 67.4 mg/kg po). The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel 5-LOX pharmacophore for the design of cyclic hydroxamic mimetics for exploitation in the development of COX-2/5-LOX inhibitory AI drugs.