Synthesis and biological evaluation of amide derivatives of (6-Chloro-2,3-dihydro-1H-inden-1-yl)acetic acid as potential anti-inflammatory agents with lower gastrointestinal toxicity.
A variety of amide derivatives of (6-chloro-2,3-dihydro-1H-inden-1-yl)acetic acid were synthesized and screened for their anti-inflammatory and related biological activities. These compounds were found to be longer acting and showed residual activity exceeding that of standard indomethacin. The studies with SKF-525A, a standard hepatic microsomal enzyme inhibitor showed that probably the test compound per se is the active species. The compound 6y showed best activity profile with ED30 of 6.45 mg/kg however this compound was found to be toxic at 100 mg/kg p.o. Though these compounds exhibited appreciable analgesic and antipyretic activities but they failed to prevent the development of secondary inflammation in adjuvant induced arthritis assay. The compound 6x showed 94% inhibition of acetic acid induced writhing. Studies showed that antagonism of TNF-alpha is not possibly involved in the mechanism of action of these compounds. However these compounds were found to have only mild ulcerogenic potential at the tested dose level of 100 mg/kg p.o. in comparison to indomethacin.
Sharma
Meenakshi
M
Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science, Pilani, India.
Ray
Saumendra Mohan
SM
D018712:Analgesics, Non-Narcotic; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001169:Arthritis, Experimental / Q000188:drug therapy; D002351:Carrageenan; D065607:Cytochrome P-450 Enzyme Inhibitors; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005334:Fever / Q000139:chemically induced / Q000517:prevention & control; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000473:pathology; D007192:Indenes / Q000737:chemistry* / Q000494:pharmacology; D007202:Indicators and Reagents; D008070:Lipopolysaccharides / Q000633:toxicity; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced
C529686:(6-chloro-2,3-dihydro-1H-inden-1-yl)acetic acid; D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007192:Indenes; D007202:Indicators and Reagents; D008070:Lipopolysaccharides; D002351:Carrageenan; D011335:Proadifen