Discovery and optimization of novel pyridines as highly potent and selective glycogen synthase kinase 3 inhibitors.

Glycogen synthase kinase-3 plays an essential role in multiple biochemical pathways in the cell, particularly in regards to energy regulation. As such, Glycogen synthase kinase-3 is an attractive target for pharmacological intervention in a variety of disease states, particularly non-insulin dependent diabetes mellitus. However, due to homology with other crucial kinases, such as the cyclin-dependent protein kinase CDC2, developing compounds that are both potent and selective is challenging. A novel series of derivatives of 5-nitro-N2-(2-(pyridine-2ylamino)ethyl)pyridine-2,6-diamine were synthesized and have been shown to potently inhibit glycogen synthase kinase-3 (GSK3). Potency in the low nanomolar range was obtained along with remarkable selectivity. The compounds activate glycogen synthase in insulin receptor-expressing CHO-IR cells and in primary rat hepatocytes, and have acceptable pharmacokinetics and pharmacodynamics to allow for oral dosing. The X-ray co-crystal structure of human GSK3-ß in complex with compound 2 is reported and provides insights into the structural determinants of the series responsible for its potency and selectivity.

Progress and development of small molecule HCV antivirals.

Hepatitis C virus (HCV) is a disease that has a growing impact worldwide. A combination therapy comprising interferon-alpha (IFNalpha) and ribavirin represents the current standard treatment for chronic HCV infection, although it has demonstrated limited success and causes some serious side effects. Promising alternative approaches toward the control of HCV infection, and the development of new antiviral agents, include the use of NS3/4A serine protease and NS5B polymerase inhibitors. Successful proof-of-concept clinical trials of the NS3/4A protease inhibitor BILN-2061 have confirmed the usefulness of a peptidomimetic product-based approach, providing impetus for the generation of improved molecules. Preclinical results from the development of HCV polymerase inhibitors, both nucleoside and non-nucleoside, are promising. This review provides an overview of recent progress in these areas, and discusses the potential of various approaches toward small molecule HCV antivirals.