AMPK

Type II diabetes mellitus is a metabolic disorder where disease progression is characterized by peripheral tissue insulin resistance, hyperglycemia, islet β-cell compensation, hyperinsulinemia, dyslipidemia, increased liver gluconeogenesis and ultimate loss of β-cell mass and function. The pathophysiological consequences of aberrant glucose and lipid metabolism are toxicity to organs including the kidney, eye, peripheral neurons, vasculature and heart. In particular, there is significant unmet medical need for new agents that delay disease progression by improving glycemic control and β-cell mass and function.

Adenosine 5' monophosphate-activated protein kinase (AMPK) is a member of the serine/threonine kinase family and serves as a key cellular energy sensor that exerts a significant role in the regulation of whole body energy levels. AMPK is regulated by numerous metabolic signals including increasing cellular AMP:ATP ratios, peripheral hormones involved in energy expenditure such as leptin, ghrelin and adiponectin, and physical exercise. AMPK activation positively regulates ATP-producing catabolic processes and negatively regulates ATP-consuming anabolic processes which leads to better control of glucose metabolism and weight.

In vivo validation of the AMPK pathway as an approach to regulate metabolic control has been demonstrated in multiple transgenic mouse models where either constitutively activated or inhibited AMPK results in increased or decreased glucose control, respectively. These observations have been further validated in obese rodent models using an AMP mimetic known to activate AMPK in vivo. Treated animals showed metabolic benefits including improved glucose tolerance, decreased hepatic glucose output, increased glucose disposal as well as decreased plasma fatty acids and triglycerides, and increased HDL cholesterol. Furthermore, these animals showed a trend in the reduction of abdominal fat.

We have used TTP Translational Technology^® ,our proprietary drug discovery engine, to discover a series of orally bioavailable, potent, small molecule activators of AMPK.