Structure-Activity Relationship and Biological Investigation of SR18292 (16), a Suppressor of Glucagon-Induced Glucose Production

Hua Lin, Kfir Sharabi, Li Lin, Claudia Ruiz, Di Zhu, Michael D. Cameron, Scott J. Novick, Patrick R. Griffin, Pere Puigserver, Theodore M. Kamenecka*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Despite a myriad of available pharmacotherapies for the treatment of type 2 diabetes (T2D), challenges still exist in achieving glycemic control. Several novel glucose-lowering strategies are currently under clinical investigation, highlighting the need for more robust treatments. Previously, we have shown that suppressing peroxisome proliferator-activated receptor gamma coactivator 1-alpha activity with a small molecule (SR18292, 16) can reduce glucose release from hepatocytes and ameliorate hyperglycemia in diabetic mouse models. Despite structural similarities in 16 to known β-blockers, detailed structure-activity relationship studies described herein have led to the identification of analogues lacking β-adrenergic activity that still maintain the ability to suppress glucagon-induced glucose release from hepatocytes and ameliorate hyperglycemia in diabetic mouse models. Hence, these compounds exert their biological effects in a mechanism that does not include adrenergic signaling. These probe molecules may lead to a new therapeutic approach to treat T2D either as a single agent or in combination therapy.

Original languageAmerican English
Pages (from-to)980-990
Number of pages11
JournalJournal of Medicinal Chemistry
Volume64
Issue number2
DOIs
StatePublished - 28 Jan 2021
Externally publishedYes

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