Discovery, Synthesis, And Structure Activity Relationships Of 20(S)-Protopanaxadiol (Ppd) Derivatives As A Novel Class Of Ampk Alpha 2 Beta 1 Gamma 1 Activators

Adenosine 5'-monophosphate-activated protein kinase (AMPK) has been demonstrated as a promising drug target due to its regulatory function in glucose and lipid metabolism. 20(S)-protopanoxadiol (PPD) was firstly identified from high throughput screening as a small molecule activator of AMPK subtype alpha 2 beta 1 gamma 1. In order to enhance its potency on AMPK, a series of PPD derivatives were synthesized and evaluated. Structure activity relationship study showed that the amine derivatives at the 24-position (groups 1 VI) can improve the potency (EC50: 0.7-2.3 mu M) and efficacy (fold: 2.5-3.8). Among them, compounds 12 and 13 exhibited the best potency (EC50: 12 and 0.7 mu M) and efficacy (fold: 3.7 and 3.8). Further study suggested the mechanism of AMPK activation may functioned at the allosteric position, resulting the inhibition of the lipid synthesis in HepG2 cell model. (C) 2014 Elsevier Masson SAS. All rights reserved.