6-amino-4-(pyrimidin-4-yl)pyridones: novel glycogen synthase kinase-3β inhibitors.

The synthesis and structure-activity relationships for a novel series of 6-amino-4-(pyrimidin-4-yl)pyridones derived from a high throughput screening hit are discussed. Optimization of lead matter afforded compounds with good potency, selectivity and central nervous system (CNS) exposure.

[1]  Jongsoon Lee,et al.  The role of GSK3 in glucose homeostasis and the development of insulin resistance. , 2007, Diabetes research and clinical practice.

[2]  Michel Goedert,et al.  GSK3 inhibitors: development and therapeutic potential , 2004, Nature Reviews Drug Discovery.

[3]  H. Bredereck,et al.  Säureamid-Reaktionen, L; Orthoamide, I Darstellung und Eigenschaften der Amidacetale und Aminalester , 1968 .

[4]  J. Ávila,et al.  GSK-3 inhibitors for Alzheimer’s disease , 2007, Expert review of neurotherapeutics.

[5]  R. Austin,et al.  A UNIFIED MODEL FOR PREDICTING HUMAN HEPATIC, METABOLIC CLEARANCE FROM IN VITRO INTRINSIC CLEARANCE DATA IN HEPATOCYTES AND MICROSOMES , 2005, Drug Metabolism and Disposition.

[6]  S. Dufresne,et al.  Synthesis, photophysics, and electrochemistry of thiophene–pyridine and thiophene–pyrimidine dyad comonomers , 2010 .

[7]  Dennis A. Smith.  Metabolism, pharmacokinetics and toxicity of functional groups : impact of chemical building blocks on ADMET , 2010 .

[8]  Simon Lovestone,et al.  The GSK3 hypothesis of Alzheimer's disease , 2008, Journal of neurochemistry.

[9]  P. Greengard,et al.  Pharmacological inhibitors of glycogen synthase kinase 3. , 2004, Trends in pharmacological sciences.

[10]  R. Jope,et al.  The multifaceted roles of glycogen synthase kinase 3β in cellular signaling , 2001, Progress in Neurobiology.

[11]  F. Nelson,et al.  Central Nervous System Pharmacokinetics of the Mdr1 P-Glycoprotein Substrate CP-615,003: Intersite Differences and Implications for Human Receptor Occupancy Projections from Cerebrospinal Fluid Exposures , 2007, Drug Metabolism And Disposition.

[12]  P. Verhoest,et al.  Moving beyond rules: the development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties. , 2010, ACS chemical neuroscience.

[13]  Simone Sciabola,et al.  High-Throughput Biochemical Kinase Selectivity Assays: Panel Development and Screening Applications , 2009, Journal of biomolecular screening.

[14]  A. Hopkins,et al.  Ligand efficiency: a useful metric for lead selection. , 2004, Drug discovery today.

[15]  A. Ougolkov,et al.  Targeting GSK-3: a promising approach for cancer therapy? , 2006, Future oncology.

[16]  A. Takashima,et al.  Role of GSK‐3β in Alzheimer's disease pathology , 2002 .

[17]  R. Obach,et al.  Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[18]  G. Müller,et al.  Small-molecule inhibitors binding to protein kinase. Part II: the novel pharmacophore approach of type II and type III inhibition , 2008, Expert opinion on drug discovery.

[19]  H. Eldar-Finkelman,et al.  Glycogen synthase kinase 3: an emerging therapeutic target. , 2002, Trends in molecular medicine.