Design, synthesis, and biological evaluation of novel sulindac derivatives as partial agonists of PPARγ with potential anti-diabetic efficacy

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a valuable drug target for diabetic treatment and ligands of PPAR gamma have shown potent anti-diabetic efficacy. However, to overcome the severe side effects of current PPAR gamma-targeted drugs, novel PPAR gamma ligands need to be developed. Sulindac, an identified ligand of PPAR gamma, is widely used in clinic as a non-steroidal anti-inflammatory drug. To explore its potential application for diabetes, we designed and synthesized a series of sulindac derivatives to investigate their structure-activity relationship as PPAR gamma ligand and potential anti-diabetic effect. We found that meta-substitution in sulindac's benzylidene moiety was beneficial to PPAR gamma binding and transactivation. Z rather than E configuration of the benzylidene double bond endowed derivatives with the selectivity of PPAR gamma activation. The indene fluorine is essential for binding and regulating PPAR gamma. Compared with rosiglitazone, compound 6b with benzyloxyl meta-substitution and Z benzylidene double bond weakly induced adipogenesis and PPAR gamma-targeted gene expression. However, 6b potently improved glucose tolerance in a diabetic mice model. Unlike rosiglitazone, 6b was devoid of apparent toxicity to osteoblastic formation. Thus, we provided some useful guidelines for PPAR gamma-based optimization of sulindac and an anti-diabetic lead compound with less side effects. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

This study highlights the importance of meta-substitution in benzylidene moiety for PPARγ binding and activation, and the essential role of indene fluorine in regulating PPARγ. Compound 6b showed significant improvement in glucose tolerance in a diabetic model and exhibited no apparent toxicity to osteoblastic formation.