J Med Chem 2002 Sep 26;45(20):4443-4459
Andersen HS, Olsen OH, Iversen LF, Sorensen AL, Mortensen SB, Christensen MS, Branner S, Hansen TK, Lau JF, Jeppesen L, Moran EJ, Su J, Bakir F, Judge L, Shahbaz M, Collins T, Vo T, Newman MJ, Ripka WC, Moller NP.
Departments of Medicinal Chemistry Research 1, 4, and 5 and Drug Metabolism, Health Care Discovery, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Malov, Denmark, Departments of Protein Structure, Protein Design, and Signal Transduction, Novo Nordisk A/S, Novo Alle, DK-2880 Bagsvaerd, Denmark, and Ontogen Corporation, 2325 Camino Vida Roble, Carlsbad, California 92009.
Reversible phosphorylation and dephosphorylation of key proteins on tyrosine residues are important parts of intracellular signaling triggered by hormones and other agents.
Recent knock-out studies in mice have identified PTP1B as a potential target for the treatment of diabetes and obesity.
As a consequence, a number of academic and industrial groups are aggressively pursuing the development of selective PTP1B inhibitors.
In addition, other protein-tyrosine phosphatases (PTPs) appear to be critically involved in major diseases such as cancer and autoimmunity.
Given the diversity of PTPs and their potential as drug targets in different diseases, we have taken a broad approach to develop active site-directed selective inhibitors of specific members of this family of enzymes.
Using a high throughput screening, we have previously identified 2-(oxalylamino)benzoic acid 3a as a relatively weak but classical competitive inhibitor of several PTPs.(4)
On the basis of our early studies, indicating that 3a might be used as a starting point for the synthesis of selective PTP inhibitors, we now present our efforts in expansion of this concept and provide here a number of new chemical scaffolds for the development of inhibitors of different members of the PTP family.
Although the core structure of these inhibitors is charged, good oral bioavailability has been observed in rat for some compounds.
Furthermore, we have observed enhancement of 2-deoxy-glucose accumulation in C2C12 cells with prodrug analogues.