Discovery and pharmacological characterization of a novel small molecule inhibitor of phosphatidylinositol-5-phosphate 4-kinase, type II, beta.
Phosphatidylinositol-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.
Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt am Main, Germany. Electronic address: marcdietrich.voss@sanofi.com.
Marc D
MD
Voss
Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt am Main, Germany.
Werngard
W
Czechtizky
Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt am Main, Germany.
Ziyu
Z
Li
Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt am Main, Germany.
Christine
C
Rudolph
Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt am Main, Germany.
Stefan
S
Petry
Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt am Main, Germany.
Harm
H
Brummerhop
Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt am Main, Germany.
Thomas
T
Langer
Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt am Main, Germany.
Alexander
A
Schiffer
Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt am Main, Germany.
Hans-Ludwig
HL
Schaefer
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D048289:Imidazolidines / Q000737:chemistry / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D011924:Rats, Zucker; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D048289:Imidazolidines; D011743:Pyrimidines; C000590176:SAR088; D054852:Small Molecule Libraries; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase
Diabetes; PIP5K2B inhibitor; Phosphatidylinositol-5-phosphate 4-kinase, type II, beta; SAR088