Discovery of novel triazole compounds as selective IL-1β releasement inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 53; p. 128415
• Main Authors: Mu, Ruixu, Zhou, Yongting, Chen, Leyuan, Wei, Huiqiang, Yu, Jingcheng, Gou, Wenfeng, Ye, Caiying, Hou, Wenbin, Li, Yiliang, Zhu, Lei
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2021
• Subjects: Anti-inflammation drug; Dose-Response Relationship, Drug; Drug Discovery; Humans; IL-1β inhibitors; Interleukin-1beta - antagonists & inhibitors; Interleukin-1beta - immunology; Molecular Structure; NLRP3 inflammasome; Novel molecules; Structure-Activity Relationship; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Anti-inflammation drug; Novel molecules; NLRP3 inflammasome; IL-1β inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.128415

[Display omitted] Inflammation and immunity are closely related to the occurrence and development of a variety of immune diseases. Although IL-1β has been identified as a key cytokine in many immune diseases, safe and specific small molecular IL-1β releasement inhibitors are still scarce and urgently required in clinic. The investigation prospect of triazoleis limited by its complicated pharmacological effect which exhibited inferior effects on IL-1β and TNF-α. Herein, 36 novel derivatives were designed and synthesized, and nearly half of the derivatives exhibited much better selectivity on IL-1β releasement inhibition as well as keep similar inhibitory activities to lead compound. In 20 μM, compound 19 exhibited IL-1β releasement inhibitory activity (IC50 = 5.489 μM) which closed to the original compound, and 4.5-fold superior selectivity (SI = 4.71) to the lead compound (SI = 0.82). A probable SAR model of triazole derivatives for IL-1β releasement inhibition and selectivity was also proposed, which might promote the discovery of more effective and specific IL-1β releasement inhibitors in the future.