Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 2, Pages 980-990Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01450
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Funding
- Charles King Postdoctoral Fellowship
- National Institute of Diabetes and Digestive and Kidney Diseases, USA [DK117655]
- National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2018-00023-C]
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Despite the availability of numerous pharmacotherapies for type 2 diabetes (T2D), challenges remain in achieving glycemic control. Novel glucose-lowering strategies are currently under clinical investigation, indicating the need for more effective treatments. A compound known as SR18292 has shown potential in reducing glucose release and improving hyperglycemia in diabetic mouse models, suggesting a new therapeutic approach for T2D.
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 beta-blockers, detailed structure-activity relationship studies described herein have led to the identification of analogues lacking beta-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.
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