Glycogen Synthase Kinase 3 Inhibitors

Title Carbocycle-based Inhibitors of Glycogen Synthase Kinase 3 A.S. Wagman et al., US Patent 6,989,382 (January 24, 2006) Assignee Chiron Corporation Utility Treatment of Type II Diabetes 

Invention Significance Glycogen synthase kinase 3 (GSK3) is 

A mixture consisting of l-bromo-5-fluoro 2-nitrobenzene (4.5 mmol), 2,4-dichlorobenzene boronic acid (4.7 mmol), Na2C03 (13.5 mmol) in benzene, and 3 ml water was treated with tetrakis(triphenylphosphine)-palladium(0) (0.2 mmol) and heated at 75°C overnight. The mixture was partitioned between EtOAc and water and the organic layer separated, then washed with brine. It was dried with MgS04 and then concentrated. A brown solid residue was recrystallized and the product isolated in 80% yield as a white solid. 

Preparation of 6-( 2-[(2, 4, -dichloro-6-nitro-l,l -biphenyl-3-yl)amino]ethyl -amino)-nicotinonitrile 

The Step 1 product (0.1 mmol) dissolved in acetonitrile was treated with 2-(2-aminoethylamino)-5-cyanopyridine (0.1 mmol) and A.A-diisopropylethylamine (0.1 mmol) and heated to 85°C overnight. The mixture was partitioned between EtOAc and water and the organic layer was dried and concentrated. The residue was purified by chromatography with silica gel using 5% methyl alcohol/CH2Cl2 and 25 mg of product isolated. 

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Selective glycogen synthase kinase inhibitors (2004BMCL413), cardiovascular agents (1996JMC2922) and inhibitors of tubulin assembly (1996BCF251, 2000TL5853) of the fused benzoheteropine type have been reported. 

In the frame of a medicinal project at J J Pharmaceutical Research and Development aimed at designing new potent and selective glycogen synthase kinase-3/i (GSK-3/3) inhibitors, the C-3 derivatization of the 1-methyl-4-[l-alkyl-lff-indol-3-yl]-lff-pyrrole-2,5-dione scaffold was explored [31]. Microwave-assisted Stille reaction of 3-chloro-l-methyl-4-[l-alkyl-lff-indol-3-yl]-lH-pyrrole-2,5-diones with (2,4-dimethoxy-5-pyrimidinyl)(tributyl) stannane at 200 °C yielded in 6 min the desired 3,4-diaryl-lff-pyrrole-2,5-diones in moderate yields (Scheme 12). 

Nserum L, Nprskov-Lauritsen L, Olesen PH. Scaffold hopping and optimization towards libraries of glycogen synthase kinase-3 inhibitors. Bioorg Med Chem Lett 2002 12 1525-8. 

Ethyl 5-chloromethyl-l,2,3-triazole-4-carboxylate 332, obtained by cyclocondensation of 3-amino-4-azidofurazan with ethyl 4-chloroacetoacetate, is converted to pyrrolidine derivative 333 in 97% yield. Heating at reflux with 1 N HC1 deprotects the carboxylic group. The obtained acid 334 is treated with carbonyldiimidazole followed by pyridine-4-carboxylic acid amidrazone to provide product 335 in 25% yield. Compound 335 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) (Scheme 52) <2003JME3333>. 

In contrast to inhibitor 1, DARPP-32 and NIPP1, which regulate signal transduction, the function of inhibitor 2 appears to be different. There is evidence that inhibitor 2 associates with PP1, as the phosphatase is newly synthesized and contributes to the proper folding of the enzyme [40]. Inhibitor 2 can thus be considered a chaperone protein. The inactive PP 1-inhibitor 2 complex can then be activated upon phosphorylation of inhibitor 2 by glycogen synthase kinase-3. Whether this process is regulated in neurons in association with synaptic activity remains unknown. 

Bhat, R., Xue, Y., Berg, S., et al. (2003) Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J. Biol. Chem., 278, 45937 5945. 

Leclerc, S., Garnier, M., Hoessel, R. (2001) et al. Indirubins inhibit glycogen synthase kinase-3 3 and CDK5/P25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer s disease. A property common to most cyclin-dependent kinase inhibitors. J. Biol. Chem., 276, 251-260. 

Meijer L, Hajolet M, Greengard P. Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol Sci 2004 25 471-80. 

Martinez A, Castro A, Dorronsoro I, et al. Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med Res Rev 2002, 22 373-84. 

Facci, L., Stevens, D. A., and Skaper, S. D. (2003). Glycogen synthase kinase-3 inhibitors protect central neurons against excitotoxicity. Neuroreport 14, 1467-1470. 

Droucheau E, Primot A, Thomas V et al (2004) Plasmodium falciparum glycogen synthase kinase-3 molecular model, expression, intracellular localisation and selective inhibitors. Biochim Biophys Acta 1697(1-2) 181-196... 

Polgar T, Baki A, Szendrei GI, Keseru GM (2005) Comparative virtual and experimental high-throughput screening for glycogen synthase kinase-3beta inhibitors. J Med Chem 48 7946-7959... 

Kaidanovich-Beilin, O., Milman, A., Weizman, A., Pick, C.G., and Eldar-Finkelman, H., 2004, Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on beta-catenin in mouse hippocampus. Biol. Psychiatry 55 781-784. 

NMDA glycine-site antagonists <03BMCL3553>, 5-aryl-pyrazolo[3,4-6]pyridazines as inhibitors of glycogen synthase kinase-3 <03BMCL1581>, and 3-arylamino- and 3-cycloalkylamino-5,6-diphenylpyridazines as ACAT inhibitors <03AP563>. 

FFA, free fatty acid GH, growth hormone GLP-1, glucagon-like protein 1 GS, glycogen synthase GSK3, glycogen synthase kinase 3 HDL, high density lipoprotein HF, heart failure IKK, inhibitor of kappa B kinase INK, c-jun N-terminal kinase EDL, low density lipoprotein Ep(a), lipoprotein little a EV, left ventricular MetS, metabolic syndrome MI, myocardial infarction... 

R. Substituted 3-lmidazo[1,2-a]pyridin-3-yl- 4-(1,2,3,4-tetrahydro-[1,4]diazepino- [6,7,1-hi]indol-7-yl)pyrrole-2,5-diones as Highly Selective and Potent Inhibitors of Glycogen Synthase Kinase-3. J. Med. Chem. 2004,47, 3934-3937. 

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