Discovery of novel carboxylesterase 2 inhibitors for the treatment of delayed diarrhea and ulcerative colitis

This study identified a lead compound 1 with a novel scaffold by high-throughput screening in our in-house library. After a comprehensive structure-activity relationship study, the optimal compound 24 was discovered as an efficient and highly selective hCES2 inhibitor (hCES2: IC50 = 6.72 μM; hCES1: IC50 > 100 μM). Further enzyme kinetics study indicated that compound 24 is a reversible inhibitor of hCES2 with competitive inhibition mode (Ki = 6.28 μM). The cell experiments showed that compound 24 could reduce the level of hCES2 in living cells (IC50 = 6.54 μM). The modeling study suggested that compound 24 fitted very well with the binding pocket of hCES2 by forming multiple interactions. Notably, compound 24 can effectively treat irinotecan-induced delayed diarrhea and DSS-induced ulcerative colitis, and its safety has also been verified in subtoxic studies. Based on the overall pharmacological and preliminary safety profiles, compound 24 is worthy of further evaluation as a novel agent for irinotecan-induced delayed diarrhea.PMID:37567318 | DOI:10.1016/j.bcp.2023.115742

Source: Biochemical Pharmacology - August 11, 2023 Category: Drugs & Pharmacology Authors: Zhijun Cao Yuxia Liu Siliang Chen Wenxin Wang Zhongcheng Yang Ya Chen Shixuan Jiao Wanqiu Huang Lianru Chen Lidan Sun Zheng Li Luyong Zhang Source Type: research