Discovery of novel triazole compounds as selective IL-113 releasement inhibitors

Inflammation and immunity are closely related to the occurrence and development of a variety of immune diseases. Although IL-113 has been identified as a key cytokine in many immune diseases, safe and specific small molecular IL-113 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-113 and TNF alpha. Herein, 36 novel derivatives were designed and synthesized, and nearly half of the derivatives exhibited much better selectivity on IL-113 releasement inhibition as well as keep similar inhibitory activities to lead compound. In 20 mu M, compound 19 exhibited IL-113 releasement inhibitory activity (IC50 = 5.489 mu M) 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-113 releasement inhibition and selectivity was also proposed, which might promote the discovery of more effective and specific IL-113 releasement inhibitors in the future.