• Biochem. Biophys. Res. Commun. · Jul 2014

    Discovery and pharmacological characterization of a novel small molecule inhibitor of phosphatidylinositol-5-phosphate 4-kinase, type II, beta.

    • Marc D Voss, Werngard Czechtizky, Ziyu Li, Christine Rudolph, Stefan Petry, Harm Brummerhop, Thomas Langer, Alexander Schiffer, and Hans-Ludwig Schaefer.
    • Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt am Main, Germany. Electronic address: marcdietrich.voss@sanofi.com.
    • Biochem. Biophys. Res. Commun. 2014 Jul 4;449(3):327-31.

    AbstractPhosphatidylinositol-5-phosphate 4-kinase, type II, beta (PIP5K2B) is linked to the pathogenesis of obesity, insulin resistance and diabetes. Here, we describe the identification of a novel pyrimidine-2,4-diamine PIP5K2B inhibitor, designated SAR088. The compound was identified by high-throughput screening and subsequently characterized in vitro and in vivo. SAR088 showed reasonable potency, selectivity and physicochemical properties in enzymatic and cellular assays. In vivo, SAR088 lowered blood glucose levels of obese and hyperglycemic male Zucker diabetic fatty rats treated for 3 weeks. Thus, SAR088 represents the first orally available and in vivo active PIP5K2B inhibitor and provides an excellent starting point for the development of potent and selective PIP5K2B inhibitors for the treatment of insulin resistance and diabetes.Copyright © 2014 Elsevier Inc. All rights reserved.

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