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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Potential Drug Targets and Progress Towards Pharmacologic Inhibition of Hepatic Glucose Production

Author(s): R. Kurukulasuriya, J. T. Link, D. J. Madar, Z. Pei, S. J. Richards, J. J. Rohde, A. J. Souers and B. G. Szczepankiewicz

Volume 10 , Issue 2 , 2003

Page: [123 - 153] Pages: 31

DOI: 10.2174/0929867033368556

Price: $65


A number of therapeutic targets are currently under investigation for inhibition of hepatic glucose production with small molecules. Antagonists of the glucagon receptor, glycogen phosphorylase, 11-β- hydroxysteroid dehydrogenase-1 and fructose 1,6-bisphosphatase are, or have been, under evaluation in human clinical trials. Other strategies, including glucocorticoid receptor antagonists and carnitine palmitoyltransferase inhibitors, are supported by proof of principle studies in man as well as rodents. Several potential targets including glucose-6-phosphatase, glucose-6-phosphatase translocase, glycogen synthase kinase-3, adenosine receptor 2B antagonists, phosphoenolpyruvate carboxykinase and pyruvate dehydrogenase kinase, have been validated by compounds that are effective in animal models. Other targets like PGC-1a and CREB have initial validation support but no medicinal chemistry has been reported.

Keywords: hepatic glucose production, diabetes, glucagon receptor antagonist, glycogen phosphorylase inhibitor, glucocorticoid receptor antagonist, gsk3 inhibitor, g-6-pase inhibitor, fructose-1,6, bisphosphatase inhibitor, hsd-1 inhibitor

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