Alkynyl phenyl heteroaromatic glucokinase activators

• Main Author: Mahaney, Paige Erin
• Format: Patent
• Language: English
• Published: 14.05.2002

Glucokinase (GK) is one of four hexokinases found in mammals [Colowick, S. P., in , Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic -cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B. in (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations (<1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial ( 10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Granner, D. K. in Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in -cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in p-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production. Para-alkynyl phenyl heteroaromatic amides which are active as glucokinase activators to increase insulin secretion which makes them useful for treating type II diabetes.