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

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.