Amide Derivatives of [5-Chloro-6-(2-chloro/fluorobenzoyl)-2-benzoxazolinone-3-yl]acetic Acids as Potential Analgesic and Anti-Inflammatory Compounds

• Published in: Archiv der Pharmazie (Weinheim) Vol. 336; no. 4-5; pp. 251 - 257
• Main Authors: Banoglu, Erden, Okçelik, Berna, Kupeli, Esra, Ünlü, Serdar, Yeşilada, Erdem, Amat, Merc?, Caturla, Joan F., Sahin, M. Fethi
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 01-07-2003; WILEY‐VCH Verlag; Wiley-VCH
• Subjects: 2-Benzoxazolinone; Acetates - chemical synthesis; Acetates - chemistry; Acetates - pharmacology; Analgesic; Analgesics; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Analgesics - toxicity; Animals; Anti-inflammatory; 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; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; COX-1; COX-2; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Cyclooxygenase Inhibitors - toxicity; Disease Models, Animal; Edema - chemically induced; Edema - drug therapy; Humans; In Vitro Techniques; Isoenzymes - antagonists & inhibitors; Isoenzymes - blood; Lethal Dose 50; Male; Medical sciences; Membrane Proteins; Mice; Neuropharmacology; Oxazoles - chemical synthesis; Oxazoles - chemistry; Oxazoles - pharmacology; Pain Measurement; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - blood; Stomach Ulcer - chemically induced; Structure-Activity Relationship; Prostaglandin-endoperoxide synthase; COX-2; Toxicity; COX-1; Gastrointestinal; Organic carbamate; Structure activity relation; Chlorine Organic compounds; Bicyclic compound; Aromatic compound; Chemical synthesis; Oxygen nitrogen heterocycle; 2-Benzoxazolinone; Human; Enzyme; Rodentia; Antiinflammatory agent; Benzene derivatives; Oral administration; Enzyme inhibitor; In vitro; Vertebrata; Mammalia; Analgesic; Mouse; Animal; Carboxamide; Fluorine Organic compounds; Oxidoreductases; Anti-inflammatory
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.200300723

In this study, we have explored the prevention of gastric side effects such as gastric lesions and bleeding while maintaining the high analgesic and anti‐inflammatory activities by the derivatization of the carboxylate moiety into amides in [5‐chloro‐6‐(2‐chloro/fluorobenzoyl)‐2‐benzoxazolinone‐3‐yl]acetic acids. We have tested the analgesic and anti‐inflammatory activities of the synthesized compounds in vivo by using p‐benzoquinone‐induced writhing test and carrageenan‐induced hind paw edema model, respectively. Compounds 3a, 3d, 3e, 3j and 3k potent analgesic and anti‐inflammatory activities without gastric lesions in the tested animals. Therefore, conversion of the carboxylate moiety into certain amide derivatives generated potent analgesic and anti‐inflammatory compounds while eliminating the gastrointestinal side effects. Cyclooxygenase (COX)‐selectivity of the active compounds was also investigated by using in vitro human whole blood assay. Compounds 3a, 3e, 3h and 3k selective inhibition of COX‐2 to some extent although the inhibitory activity was not very potent.