Structural modification based on the diclofenac scaffold: Achieving reduced colitis side effects through COX-2/NLRP3
Zhiran Ju1, Junde Xu1, Keshuang Tang1
1Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, China.
Abstract:
COX-2/NLPR3-targeted therapy might be beneficial for the inflammation diseases. To discover novel anti-inflammatory compounds with favorable safety profiles, three new series of non-carboxylic diclofenac analogues bearing various ring systems, such as oxadiazoles 4a-4w, triazoles 6a-6m, and cyclic imides 7a and 7b, were synthesized. The synthesized analogues were evaluated for their inhibitory activity against COX-2 enzyme. Among them, compound 6k exhibited potent selective COX-2 inhibition (IC50 = 1.53 μM; selectivity ((IC50 (COX-1)/IC50(COX-2) = 17.19). Treatment with compound 6k effectively suppressed the NF-κB/NLRP3 signaling pathway, resulting in reduced expression of pro-inflammatory factors. The in vivo ulcerative colitis assay demonstrated that compound 6k significantly ameliorated histological damages and showed strong protection against DSS-induced acute colitis. The collected results indicated that compound 6k displays anti-inflammatory activity through COX-2/NLRP3 inhibition. Therefore, compound 6k represents a promising candidate for further development as a new lead compound with reduced colitis side effects.
More Related Videos
08:58Analyzing Beneficial Effects of Nutritional Supplements on Intestinal Epithelial Barrier Functions During Experimental Colitis
Published on: January 5, 2017
13:38Synthesis and Characterization of an Aspirin-fumarate Prodrug that Inhibits NFκB Activity and Breast Cancer Stem Cells
Published on: January 18, 2017
Related Concept Videos
Drugs for Treatment of Ulcerative Colitis in IBD
Drugs for Treatment of Crohn's Disease in IBD Using Immunomodulatory Agents
Drugs for Treatment of Crohn's Disease in IBD Using Glucocorticoids
Inflammatory Bowel Disease IV: Pharmacological Management
Pharmacologic...
Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF
Drugs for Peptic Ulcer Disease: Prostaglandin Analogs as Mucosal Protective Agents
Non-steroidal anti-inflammatory drugs (NSAIDs) can induce peptic ulcers by inhibiting cyclooxygenase, decreasing...
