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

doi:10.1021/acs.jmedchem.0c01450

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 journal › Article › peer-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 language	American English
Pages (from-to)	980-990
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	2
DOIs	https://doi.org/10.1021/acs.jmedchem.0c01450
State	Published - 28 Jan 2021
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by a Charles King Postdoctoral Fellowship to K.S. and by the National Institute of Diabetes and Digestive and Kidney Diseases, USA (DK117655 to P.P. and P.R.G.). K determinations, receptor binding profiles, and agonist and/or antagonist functional data were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2018-00023-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, Ph.D, at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. i

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title = "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.",

author = "Hua Lin and Kfir Sharabi and Li Lin and Claudia Ruiz and Di Zhu and Cameron, {Michael D.} and Novick, {Scott J.} and Griffin, {Patrick R.} and Pere Puigserver and Kamenecka, {Theodore M.}",

note = "Funding Information: This work was supported by a Charles King Postdoctoral Fellowship to K.S. and by the National Institute of Diabetes and Digestive and Kidney Diseases, USA (DK117655 to P.P. and P.R.G.). K determinations, receptor binding profiles, and agonist and/or antagonist functional data were generously provided by the National Institute of Mental Health{\textquoteright}s Psychoactive Drug Screening Program, Contract # HHSN-271-2018-00023-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, Ph.D, at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. i Publisher Copyright: {\textcopyright} ",

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AU - Sharabi, Kfir

AU - Lin, Li

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AU - Zhu, Di

AU - Cameron, Michael D.

AU - Novick, Scott J.

AU - Griffin, Patrick R.

AU - Puigserver, Pere

AU - Kamenecka, Theodore M.

N1 - Funding Information: This work was supported by a Charles King Postdoctoral Fellowship to K.S. and by the National Institute of Diabetes and Digestive and Kidney Diseases, USA (DK117655 to P.P. and P.R.G.). K determinations, receptor binding profiles, and agonist and/or antagonist functional data were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2018-00023-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, Ph.D, at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. i Publisher Copyright: ©

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N2 - 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.

AB - 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.

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

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