Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes mellitus

J Med Chem. 2012 Feb 9;55(3):1318-33. doi: 10.1021/jm2014887. Epub 2012 Jan 24.


Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic β-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.

MeSH terms

  • Allosteric Site
  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dogs
  • Enzyme Activators / chemical synthesis*
  • Enzyme Activators / pharmacokinetics
  • Enzyme Activators / pharmacology
  • Glucokinase / metabolism*
  • Haplorhini
  • Hepatocytes / metabolism*
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology
  • Imidazoles / chemical synthesis*
  • Imidazoles / pharmacokinetics
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Insulin-Secreting Cells / metabolism
  • Male
  • Models, Molecular
  • Nicotinic Acids / chemical synthesis*
  • Nicotinic Acids / pharmacokinetics
  • Nicotinic Acids / pharmacology
  • Organic Anion Transporters / metabolism
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tissue Distribution


  • Blood Glucose
  • Enzyme Activators
  • Hypoglycemic Agents
  • Imidazoles
  • Nicotinic Acids
  • Organic Anion Transporters
  • 6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid
  • Glucokinase