Discovery of Orally Bioavailable Purine-Based Inhibitors of the Low-Molecular-Weight Protein Tyrosine Phosphatase

Obesity-associated insulin resistance
plays a central role in the
pathogenesis of type 2 diabetes. A promising approach to decrease
insulin resistance in obesity is to inhibit the protein tyrosine phosphatases
that negatively regulate insulin receptor signaling. The low-molecular-weight
protein tyrosine phosphatase (LMPTP) acts as a critical promoter of
insulin resistance in obesity by inhibiting phosphorylation of the
liver insulin receptor activation motif. Here, we report development
of a novel purine-based chemical series of LMPTP inhibitors. These
compounds inhibit LMPTP with an uncompetitive mechanism and are highly
selective for LMPTP over other protein tyrosine phosphatases. We also
report the generation of a highly orally bioavailable purine-based
analogue that reverses obesity-induced diabetes in mice.