Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus. Issue 9 (1st May 2017)

• Record Type: Journal Article
• Authors: Xu, Jiayi; Lin, Songnian; Myers, Robert W.; Trujillo, Maria E.; Pachanski, Michele J.; Malkani, Sunita; Chen, Hsuan-shen; Chen, Zhesheng; Campbell, Brian; Eiermann, George J.; Elowe, Nadine; Farrer, Brian T.; Feng, Wen; Fu, Qinghong; Kats-Kagan, Roman; Kavana, Michael; McMasters, Daniel R.; Mitra, Kaushik; Tong, Xinchun; Xu, Libo; Zhang, Fengqi; Zhang, Rui; Addona, George H.; Berger, Joel P.; Zhang, Bei; Parmee, Emma R.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 9(2017)
• Page Start: 2063
• Page End: 2068
• Publication Date: 2017-05-01
• Subjects: Glucokinase -- Glucokinase activator (GKA) -- Hexokinase IV -- Glucose homeostasis -- Glucose metabolism -- Hepatoselective -- Hepatospecific -- Liver preferring -- Type II Diabetes Mellitus -- Diabetes -- Pyridine-2-carboxamide; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.10.088
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic β-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound6 . GKA6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10 mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.