Structure-Activity Relationship and Biological Investigation of SR18292 (16), a Suppressor of Glucagon-Induced Glucose Production.
J Med Chem
; 64(2): 980-990, 2021 01 28.
Article
in En
| MEDLINE
| ID: mdl-33434430
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 ß-blockers, detailed structure-activity relationship studies described herein have led to the identification of analogues lacking ß-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Glucagon
/
Propanols
/
Gluconeogenesis
/
Hypoglycemic Agents
/
Indoles
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2021
Document type:
Article
Affiliation country:
United States