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


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.

SUBMITTER: Lin H 

PROVIDER: S-EPMC7869975 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Structure-Activity Relationship and Biological Investigation of SR18292 (<b>16</b>), a Suppressor of Glucagon-Induced Glucose Production.

Lin Hua H   Sharabi Kfir K   Lin Li L   Ruiz Claudia C   Zhu Di D   Cameron Michael D MD   Novick Scott J SJ   Griffin Patrick R PR   Puigserver Pere P   Kamenecka Theodore M TM  

Journal of medicinal chemistry 20210112 2


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, <b>16</b>) can reduce glucose release from hepatocytes and amelio  ...[more]

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