Obesity and comorbid type 2 diabetes represent a frequent and growing global problem. The insulin resistance syndrome was first described in 1988 and contributes to both conditions and indeed is generally accepted to represent a pathophysiological link between the two. It is estimated that this syndrome affects 70 to 80 million Americans and is characterized by a failure of insulin to stimulate glucose utilization and uptake into tissues. Considerable attention has been paid to the development of molecules able to reduce insulin resistance. LeadDiscovery has recently published a report overviewing the therapeutic potential of one class of molecules that fit this profile, the GSK-3 inhibitors. This class of drug stands to play a major role in the treatment of Alzheimer's disease, stroke and bipolar disorder as well as diabetes.

GSK-3 is a constitutively active kinase that maintains enzymes such as glycogen synthase in a phosphorylated state. One of its other targets is IRS-1, hyperphosphorylation of which attenuates insulin signaling. A number of protein tyrosine phosphatases including PTPalpha, LAR, CD45, PTPepsilon, SHP2, and PTP1B also modulate insulin signaling. These enzymes phosphorylate the insulin receptor causing its inactivation. The most convincing data support a critical role for PTP1B in insulin action. PTP1B knockout mice are not only insulin sensitive but also maintain euglycemia (in the fed state), with one-half the level of insulin observed in wild-type littermates. Further studies have also implicated PTP1B in leptin resistance and this may explain in part why deleting the PTP1B gene confers resistance to diet-induced obesity when fed a high-fat diet. PTPs are also implicated in a wide variety of other disorders, including cancer and therefore inhibitors of this family of enzymes may be of use considerable use.

A number of companies have developed such PTP inhibitors including Kinetek, Ontogen and Ceptyr (for the treatment of cancer) and Kaken Pharmaceutical (for the treatment of insulin resistance). Many PTP inhibitors identified to date however are peptide-based and contain a highly charged phosphate-mimicking component. These compounds usually lack membrane permeability and this limits their utility in the inhibition of intracellular phosphatases. SUGEN have recently addressed this issue having used structure-based design and modeling techniques to explore catalytic-site directed, reversible inhibitors of PTPs. Employing a non-charged phosphate mimic and non-peptidyl structural components, Huang et al successfully designed and synthesized a novel series of trifluoromethyl sulfonyl and trifluoromethyl sulfonamido compounds as PTP inhibitors. This is the first time that an uncharged phosphate mimic is reported in the literature for general, reversible, and substrate-competitive inhibition of PTPs. This will hopefully provide a paradigm for the development of phosphatase inhibitors that enter cells and modify signal transduction thereby offering a treatment approach to a variety of serious and unmet conditions.

Entry date Thursday, April 24, 2003

Adapted from Huang et al, Bioorg Med Chem 2003 Apr;11(8):1835-49

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