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Development of Novel Alkene Oxindole Derivatives As Orally Efficacious AMP-Activated Protein Kinase Activators.


ABSTRACT: Adenosine 5'-monophosphate-activated protein kinase (AMPK) is emerging as a promising drug target for its regulatory function in both glucose and lipid metabolism. Compound PT1 (5) was originally identified from high throughput screening as a small molecule activator of AMPK through the antagonization of the autoinhibition in ? subunits. In order to enhance its potency at AMPK and bioavailability, structure-activity relationship studies have been performed and resulted in a novel series of AMPK activators based on an alkene oxindole scaffold. Following their evaluation in pharmacological AMPK activation assays, lead compound 24 was identified to possess improved potency as well as favorable pharmacokinetic profile. In the diet-induced obesity (DIO) mouse model, compound 24 was found to improve glucose tolerance and alleviate insulin resistance. The in vitro and in vivo data for these alkene oxindoles warrant further studies for their potential therapeutic medications in metabolic associated diseases.

SUBMITTER: Yu LF 

PROVIDER: S-EPMC4027511 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Development of Novel Alkene Oxindole Derivatives As Orally Efficacious AMP-Activated Protein Kinase Activators.

Yu Li-Fang LF   Li Yuan-Yuan YY   Su Ming-Bo MB   Zhang Mei M   Zhang Wei W   Zhang Li-Na LN   Pang Tao T   Zhang Run-Tao RT   Liu Bing B   Li Jing-Ya JY   Li Jia J   Nan Fa-Jun FJ  

ACS medicinal chemistry letters 20130325 5


Adenosine 5'-monophosphate-activated protein kinase (AMPK) is emerging as a promising drug target for its regulatory function in both glucose and lipid metabolism. Compound PT1 (5) was originally identified from high throughput screening as a small molecule activator of AMPK through the antagonization of the autoinhibition in α subunits. In order to enhance its potency at AMPK and bioavailability, structure-activity relationship studies have been performed and resulted in a novel series of AMPK  ...[more]

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