2. Academic Validation
  3. Discovery of AdipoRon analogues as novel AMPK activators without inhibiting mitochondrial complex I

Discovery of AdipoRon analogues as novel AMPK activators without inhibiting mitochondrial complex I

  • Eur J Med Chem. 2020 Aug 15;200:112466. doi: 10.1016/j.ejmech.2020.112466.
Geng Sun 1,  Yanping You 1,  Haobin Li 1,  Yalong Cheng 1,  Ming Qian 1,  Xinyu Zhou 1,  Haoliang Yuan 1,  Qing-Long Xu 1,  Liang Dai 1,  Pengfei Wang 1,  Keguang Cheng 2,  Xiaoan Wen 3,  Caiping Chen 4
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin, 541004, China.
  • 3 Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: wxagj@cpu.edu.cn.
  • 4 Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. Electronic address: caiping.chen@cpu.edu.cn.
PMID: 32512485 DOI: 10.1016/j.ejmech.2020.112466
Abstract

Activation of AMPK emerges as a potential therapeutic approach to metabolic diseases. AdipoRon is claimed to be an Adiponectin Receptor Agonist that activates AMPK through Adiponectin Receptor 1 (AdipoR1). However, AdipoRon also exhibits moderate inhibition of mitochondrial complex I, leading to increased risk of lactic acidosis. In order to find novel AdipoRon analogues that activate AMPK without inhibition of complex I, 27 analogues of AdipoRon were designed, synthesized and biologically evaluated. As results, benzyloxy arylamide B10 was identified as a potent AMPK Activator without inhibition of complex I. B10 dose-dependently improved glucose tolerance in normal mice, and significantly lowered fasting blood glucose level and ameliorated Insulin resistance in db/db diabetic mice. More importantly, unlike the pan-AMPK activator MK-8722, B10 did not cause cardiac hypertrophy, probably owing to its selective activation of AMPK in the muscle tissue but not in the heart tissue. Together, B10 represents a novel class of AMPK activators with promising therapeutic potential against Metabolic Disease.

Keywords

AMPK; Activator; AdipoRon; Complex I; Hypoglycemic action.

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