[HXK4_HUMAN] Defects in GCK are the cause of maturity-onset diabetes of the young type 2 (MODY2) [MIM:125851]; also shortened MODY-2. MODY is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:602485]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.
[HXK4_HUMAN] Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage.
A novel class of 3,6-disubstituted 2-pyridinecarboxamide derivatives was designed based on X-ray analysis of the 2-aminobenzamide lead class. Subsequent chemical modification led to the discovery of potent GK activators which eliminate potential toxicity concerns associated with an aniline group of the lead structure. Compound 7 demonstrated glucose lowering effect in a rat OGTT model.
Discovery of novel 3,6-disubstituted 2-pyridinecarboxamide derivatives as GK activators.,Mitsuya M, Kamata K, Bamba M, Watanabe H, Sasaki Y, Sasaki K, Ohyama S, Hosaka H, Nagata Y, Eiki J, Nishimura T Bioorg Med Chem Lett. 2009 May 15;19(10):2718-21. Epub 2009 Mar 29. PMID:19362831
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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↑ Mitsuya M, Kamata K, Bamba M, Watanabe H, Sasaki Y, Sasaki K, Ohyama S, Hosaka H, Nagata Y, Eiki J, Nishimura T. Discovery of novel 3,6-disubstituted 2-pyridinecarboxamide derivatives as GK activators. Bioorg Med Chem Lett. 2009 May 15;19(10):2718-21. Epub 2009 Mar 29. PMID:19362831 doi:10.1016/j.bmcl.2009.03.137