title: 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 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 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.
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Yu
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Li
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Ming-Bo
authors.initials: MB
authors.lastname: Su
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Mei
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Zhang
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Pang
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Run-Tao
authors.initials: RT
authors.lastname: Zhang
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Li
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, P. R. China.
authors.forename: Fa-Jun
authors.initials: FJ
authors.lastname: Nan
keywords: AMPK activator; DIO mouse model; alkene oxindole; diabetes; insulin sensitivity