Discovery of liver-selective glucokinase activators comprising N-(4-alkylthiazol-2-yl)benzamides and N-(3-alkyl-1,2,4-thiadiazol-5-yl)benzamides for the treatment of metabolic disorders

Abstract

Glucokinase (“GK”) plays a critical role in regulating glucose homeostasis within the body. Proof-of-concept animal models demonstrated that small molecule GK activation enhances glucose uptake and utilization by various tissues, including liver and pancreas. Accordingly, glucokinase activators (“GKAs”) were extensively explored as a potential therapy for carbohydrate metabolism disorders. Yet in clinical trials, mechanism-based hypoglycemia was often observed when GK was activated in both liver and pancreas. One ameliorative approach was to pursue hepatocentric GKAs. Described herein is a series of liver selective GKAs based on N-(4-alkylthiazol-2-yl)benzamide and N-(3-alkyl-1,2,4-thiadiazol-5-yl)benzamide pharmacophores. Optimization efforts revealed that enhanced liver selectivity could be achieved by replacing diethylphosphonate group (compound 1) with a dimethylphosphinate (compound 3). Due to mutagenicity of a putative aminoheterocycle metabolite of 3, subsequent amines were triaged using SOS chromotest. Efforts ultimately led to identification of thiazole-based compounds 11–13, which exhibited significant glucose lowering in acute DIO (“diet-induced obese”) mouse OGTT (“oral glucose tolerance test”) studies. However, insulin secretion was observed at higher doses, and thus the desired therapeutic window between efficacy and insulin secretion was not achieved. Thiadiazole-based compounds were then explored to assess whether this modification could obviate the insulin secretion observed with the thiazole series. Several thiadiazoles were discovered with exceptionally high liver selectivity and drug liver concentrations when evaluated in mouse pharmacokinetic studies. Compounds 17–19 and 20–22 were advanced into acute DIO OGTT studies, but were inactive. Notably, a relatively higher degree of plasma protein binding was observed for the non-efficacious vs. efficacious compounds.