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Sarabu, R. et al.

Ramakanth Sarabu, Fred T. Bizzarro, Wendy L. Corbett, Mark T. Dvorozniak, Wanping Geng, Joseph F. Grippo, Nancy-Ellen Haynes, Stanley Hutchings, Lisa Garofalo, Kevin R. Guertin, Darryl W. Hilliard, Marek Kabat, Robert F. Kester, Wang Ka, Zhenmin Liang, Paige E. Mahaney, Linda Marcus, Franz M. Matschinsky, David Moore, Jagdish Racha, Roumen Radinov, Yi Ren, Lida Qi, Michael Pignatello, Cheryl L. Spence, Thomas Steele, John Tengi, Joseph Grimsby, Fred T. Bizzarro, Wendy L. Corbett, Mark T. Dvorozniak, Wanping Geng, Joseph F. Grippo, Nancy-Ellen Haynes, Stanley Hutchings, Lisa Garofalo, Kevin R. Guertin, Darryl W. Hilliard, Marek Kabat, Robert F. Kester, Wang Ka, Zhenmin Liang, Paige E. Mahaney, Linda Marcus, Franz M. Matschinsky, David Moore, Jagdish Racha, Roumen Radinov, Yi Ren, Lida Qi, Michael Pignatello, Cheryl L. Spence, Thomas Steele, John Tengi, Joseph Grimsby,

Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients.

Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.[1]

References

Discovery of piragliatin--first glucokinase activator studied in type 2 diabetic patients. Sarabu, R., Bizzarro, F.T., Corbett, W.L., Dvorozniak, M.T., Geng, W., Grippo, J.F., Haynes, N.E., Hutchings, S., Garofalo, L., Guertin, K.R., Hilliard, D.W., Kabat, M., Kester, R.F., Ka, W., Liang, Z., Mahaney, P.E., Marcus, L., Matschinsky, F.M., Moore, D., Racha, J., Radinov, R., Ren, Y., Qi, L., Pignatello, M., Spence, C.L., Steele, T., Tengi, J., Grimsby, J. J. Med. Chem. (2012) [Pubmed]

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