Identification of novel benzimidazole derivatives as highly potent AMPK activators with anti-diabetic profiles

Diabetes is a global healthcare problem that affects more than 400 million people worldwide. Treatment for type 1 and 2 diabetes is expected by targeting adenosine monophosphate activated protein kinase, AMPK, a well-known master regulator of glucose. Many pharmaceutical companies have tried to identify AMPK activators but few direct AMPK activators with high potency for the 132-AMPK isoform, which is important for glucose homeostasis, have been found. In addition, their chemical structure is limited to benzimidazole or indole de-rivatives bearing an aromatic substituent at the C5 position of the core structure. We describe herein our efforts to identify novel benzimidazole derivatives that directly activate the 132-AMPK isoform. Our newly designed activator 14d bearing a 1-amino indanyl moiety at the C5 position of the core exhibited high in vitro potency and good pharmacokinetic profiles. A single oral dosing of 14d showed dose-dependent activation of AMPK and blood-glucose-lowering effects was observed in a diabetic animal model. In addition, chronic AMPK activation with 14d led to dose-dependent reduction in HbA1c of the animal model.