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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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Lin H,Sharabi K,Lin L,Ruiz C,Zhu D,Cameron MD,Novick SJ,Griffin PR,Puigserver P,Kamenecka TM

doi

10.1021/acs.jmedchem.0c01450

subject

Has Abstract

pub_date

2021-01-28 00:00:00

pages

980-990

issue

2

eissn

0022-2623

issn

1520-4804

journal_volume

64

pub_type

杂志文章

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