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Recent patent applications have described novel chemical structures that do not fit into either of the above categories. Benzimidazoles (e.g. 30) [40] and quinazolines (e.g. 31) have been claimed as GKAs [41].

The vital role of GK in glucose homeostasis has been established for some time. Developments over the last decade, including the discovery of the regulatory function of GKRP, identification of maturity-onset diabetes of the young (MODY-2-), permanent neonatal diabetes (PNDM-) and (Persistent Hyperinsulinemic Hypoglycemia of Infancy) PHHI-related GK mutations, and the identification of novel GKAs and their co-crystal structures with GK, have radically improved our knowledge of GK structure and function. The structural categories of GKAs revealed thus far can be categorized as either carbon/nitrogen-centered, aromatic ring-centered activators, or a few special cases that do not fit into either category. These categories of GKAs seem to make comparable polar and non-polar interactions at the allosteric binding site, in spite of their considerable differences in structure. More significantly, in various animal models of T2D, GKAs have exhibited beneficial effects on glucose homeostasis, due to a dual effect of improving glucose utilization in the liver and glucose-dependent insulin secretion in pancreatic p-cells. Nevertheless, possible unwanted side effects, such as hypoglycemia, nausea, accumulation of fat in the liver, or even liver toxicity must be taken into consideration. The impact of GKA therapy on glycemic control in T2D patients and particularly their differentiation to the extensively prescribed sulfonylureas, is anxiously awaited.

REFERENCES

[1] F. M. Matschinsky, M. A. Magnuson, D. Zelent, T. L. Jetton, N. Doliba, Y. Han, R. Taub and J. Grimsby, Diabetes, 2006, 55, 1.

[2] R. Sarabu and J. Grimsby, Curr. Opin. Drug Disc. Dev., 2005, 8, 631.

[3] F. M. Matschinsky, Curr. Diabetes Rep., 2005, 5, 171.

[4] T. Keitzmann and G. K. Ganjam, Expert Opin. Ther. Patents, 2005, 15, 705.

[5] A. C. Storer and A. Cornish-Bowden, Biochem. J., 1977, 165, 61.

[6] K. E. Neet, R. P. Keenan and P. S. Tippett, Biochem, 1990, 29, 770.

[7] J. Grimsby, R. Sarabu, W. L. Corbett, N. E. Haynes, F. T. Bizzarro, J. W. Coffey, K. R. Guertin, D. W. Hilliard, R. F. Kester, P. E. Mahaney, L. Marcus, L. Qi, C. L. Spence,

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