PKC Inhibition and Diabetic Complications

Jose   A.   Nogueira-Machado; Adriana   A.   Bosco

doi:10.2174/187221408784534259

Abstract

Hyperglycemia activates several signaling pathways associated with vascular complications in diabetes. Hyperfunction of the diacylglycerol - protein kinase C (DAG-PKC) pathway can lead to enhanced vascular permeability, endothelial cell activation and expression of leukocyte adhesion molecules, altered blood flow and abnormal growth factor signaling. One of the most important approaches aimed at modulating these adverse effects involves the inhibition of PKC, and several inhibitory compounds have been proposed including ruboxistaurin (Eli Lilly & Co.), PKC412 and PKC412-A (Novartis Pharmaceuticals). Other patents with similar function has also been proposed such as substituted pyrrolines kinases inhibitors (US200698710B2; US2006020576A1; WOO4094422A1; US2006987110) modulation of angiogenesis (W007035782A2; US20070141040A1). This present approach intends to modulate of angiogensis by the inhibition of PKC beta as an monotherapy or in combination with other antioangiogenic compounds. Some of these compounds are currently tested in a clinical trial while other are on intensive investigation. This brief review considers therapeutic strategies with new drugs and/or new approaches using PKC inhibitors to treat diabetic complications.

Keywords: Diabetes, vascular complications, angiogenesis, PKC inhibitors, VEGF inhibitors, ruboxistaurin, PKC 142, PKC 142-A