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Leucine-rich repeat kinase 2 inhibitors: a review of recent patents (2011 – 2013)

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Bibliography

  • Ross OA, Farrer MJ. Pathophysiology, pleiotropy and paradigm shifts: genetic lessons from Parkinson's disease. Biochem Soc Trans 2005;33:586-90
  • Davie CA. A review of Parkinson's disease. Br Med Bull 2008;86:109-27
  • Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79:368-78
  • Savitt JM, Dawson VL, Dawson TM. Diagnosis and treatment of Parkinson disease: molecule to medicine. J Clin Invest 2006;116:1744-54
  • Zimprich A, Biskup S, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601-7
  • Berwick DC, Harvey K. LRRK2 signaling pathways: the key to unlocking neurodegeneration? Trends Cell Biol 2011;21:257-65
  • Lang AE, Lozano AM. Parkinson's disease. Second of two parts. N Engl J Med 1998;339:1044-53
  • Lang AE, Lozano AM. Parkinson's disease. Second of two parts. N Engl J Med 1998;339:1130-43
  • Thanvi B, Lo N, Robinson T, et al. Levodopa-induced dyskinesia in Parkinson's disease: clinical features, pathogenesis, prevention and treatment. Postgrad Med J 2007;83:384-8
  • Covy JP, Giasson BI. Alpha-Synuclein, leucine-rich repeat kinase 2, and manganese in the pathogenesis of Parkinson disease. Neurotoxicology 2011;32:622-9
  • Harrdy J, Lewis P, Revesz T, et al. The genetics of Parkinson's syndromes: a critical review. Curr Opin Genet Dev 2009;19:254-65
  • Schulte C, Gasser T. Genetic basis of Parkinson's disease: inheritance, penetrance, and expression. Appl Clin Genet 2011;4:67-80
  • Thomas B, Beal MF. Parkinson's disease. Hum Mol Genet 2007;16:R184-94
  • Martin I, Dawson VL, Dawson TM. Recent advances in the genetics of Parkinson's disease. Annu Rev Genomics Hum Genet 2011;12:301-25
  • Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that causes PARK8-linked Parkinson's disease. Neuron 2004;44:595-600
  • Mata IF, Wedemeyer WJ, Farrer MJ, et al. LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci 2006;29:286-93
  • Taylor JP, Mata IF, Farrer MJ. LRRK2: a common pathway for parkinsonism, pathogenesis and prevention? Trends Mol Med 2006;12:76-82
  • Farrer M, Stone J, Mata IF, et al. LRRK2 mutations in Parkinson disease. Neurology 2005;65:738-40
  • Zabetian CP, Samii A, Mosley AD, et al. A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations. Neurology 2005;65:741-4
  • Marin I. The Parkinson disease gene LRRK2: evolutionary and structural insights. Mol Biol Evol 2006;23:2423-33
  • Li X, Tan Y, Poulose S, et al. Leucine-rich repeat kinase 2 (LRRK2)/PARK8 possesses GTPase activity that is altered in familial Parkinson's disease R1441C/G mutants. J Neurochem 2007;103:238-47
  • Biskup S, Moore DJ, Celsi F, et al. Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol 2006;60:557-69
  • Giasson BI, Covy JP, Bonini NM, et al. Biochemical and pathological characterization of LRRK2. Ann Neurol 2006;59:315-22
  • Lewis PA, Manzoni C. LRRK2 and human disease: a complicated question or a question of complexes. Sci Signal 2012;5:pe2
  • Mata IF, Wedemeyer WJ, Farrer MJ, et al. LRRK2 in Parkinson's disease: protein domains and functional insights. Trends Neurosci 2006;29:286-93
  • Anand VS, Braithwaite SP. LRRK2 in Parkinson's disease: biochemical functions. FEBS J 2009;276:6428-35
  • Civiero L, Vancraenenbroeck R, Belluzzi E, et al. Biochemical characterization of highly purified Leucine rich repeat kinases 1 and 2 demonstrates formation of homodimers. PLoS One 2012;7:e343372
  • Mills RD, Terrence D, Mulhern TD, et al. Analysis of LRRK2 accessory repeat domains: prediction of repeat length, number and sites of Parkinson's disease mutations. Biochem Soc Trans 2012;40:1086-9
  • Biskup S, West AB. Zeroing in on LRRK2-linked pathogenic mechanisms in Parkinson's disease. Biochim Biophys Acta 2009;1792:625-33
  • Seol W. Biochemical and molecular features of LRRK2 and its pathophysiological roles in Parkinson's disease. BMB Rep 2010;43:233-44
  • Smith WW, Pei Z, Jiang H, et al. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 2006;9:1231-3
  • West AB, Moore DJ, Biskup S, et al. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 2005;102:16842-7
  • Smith WW, Pei Z, Jiang H, et al. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci USA 2005;102:18676-81
  • Greggio E, Cookson MR. Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN Neuro 2009;1:e00002
  • Kumar A, Cookson MR. Role of LRRK2 kinase dysfunction in Parkinson's disease. Expert Rev Mol Med 2011;13:e20
  • Kramer T, Lo Monte F, Goering S, et al. Small molecule kinase inhibitors for LRRK2 and their application to Parkinson's disease models. ACS Chem Neurosci 2012;3:151-60
  • Deng X, Choi HG, Buhrlage SJ, et al. Leucine-rich repeat kinase 2 inhibitors: a patent review (2006-2011). Expert Opin Ther Patents 2012;22:1415-26
  • Cookson MR. The role of leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease. Nat Rev Neurosci 2010;11:791-7
  • Anand VS, Braithwaite SP. LRRK2 in Parkinson's disease: biochemical functions. FEBS J 2009;276:6428-35
  • Vancraenenbroeck R, Lobbestael E, De Maeyer M, et al. Kinases as targets for Parkinson's disease: from genetics to therapy. CNS Neurol Disord Drug Targets 2011;10:724-40
  • Benedetto A, Au C, Aschner M. Manganese-induced dopaminergic neurodegeneration: insights into mechanisms and genetics shared with Parkinson's disease. Chem Rev 2009;109:4862-84
  • Cellzome AG, Germany. Method for identification of an LRRK2 (leucine-rich repeat kinase 2)-interacting compound. WO2007104763A1
  • Cellzome Ltd, UK. Preparation of substituted pyrimidinediamines as LRRK2 inhibitors for treating neurodegenerative disease. WO2009127642A2
  • Ramsden N, Perrin J, Ren Z, et al. Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons. ACS Chem Biol 2011;6:1021-8
  • Elan Pharmaceuticals, Inc. USA. Screening methods of synucleinopathic disease. WO2012074882A2
  • Elan Pharmaceuticals, Inc. USA. Cinnoline derivatives has LRRK2 inhibitors. WO2012162254A1
  • Hudkins RL, Diebold JL, Tao M, et al. Mixed-lineage kinase 1 and mixed-lineage kinase 3 subtype-selective dihydronaphthy [3,4-a]pyrrole [3,4-c]carbazole-5-ones: optimization, mixed lineage kinase 1 crystallography, and oral in vivo activity in 1-methyl-4-phenyltetrahydropyridine models. J Med Chem 2008;51:5680-9
  • Garofalo AW, Adler M, Aubele DL, et al. Novel cinnoline-base inhibitors of LRRK2 kinase activity. Bioorg Med Chem Lett 2013;23:71-4
  • Dzamko N, Deak M, Hentati F, et al. Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser910/Ser935, disruption of 14-3-3 binding and altered cytoplasmic localization. Biochem J 2010;430:405-13
  • Lobbestael E, Zhao J, Rudenko LN, et al. Identification of protein phosphatase 1 as a regulator of the LRRK2 phosphorylation cycle. Biochem J 2013;456:119-28
  • Genentech Inc. and Medical Research Council Technology. Substituted pyrazolopyridine compounds capable of inhibiting one or more kinases, more particularly LRRK2 inhibition. US20120295883A1
  • Genentech Inc. and Medical Research Council Technology. Substituted pyrazolopyridine compounds capable of inhibiting one or more kinases, more particularly LRRK2 inhibition. WO2012038743A1
  • Lovitt B, Vanderporten EC, Sheng Z, et al. Differential effects of divalent manganese and magnesium on the kinase activity of leucine-rich repeat kinase 2 (LRRK2). Biochemistry 2010;49:3092-100
  • Chen H, Chan B, Drummond J, et al. Discovery of selective LRRK2 inhibitors guided by computational analysis and molecular modeling. J Med Chem 2012;55:5536-45
  • Estrada AA, Liu X, Baker-Glenn C, et al. Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem 2012;55:9416-33
  • Genosco and Oscotec, Inc. Pyrido [4,3-d]pyrimidine-5-one derivatives as multikinase inhibitors with LRRK2 activity. WO2011053861A
  • Genosco and Oscotec, Inc. Pyrido [4,3-d]pyrimidine-5-one derivatives as multikinase inhibitors with LRRK2 activity. US8404677B2; 2013
  • Genosco and Oscotec, Inc. A new group of protein kinase inhibitors, pyrrolopyrimidine and pyrazolopyrimidine derivatives with LRRK2 activity. WO2011060295A
  • Glaxo Group Ltd. 2-Arylmethyloxy-5-substituent-N-arylbenzamides as selective LRRK2 inhibitors. WO2011038572A1
  • Glaxo Group Ltd. 2-Arylmethyloxy-4,5-disubstituent-N-arylbenzamides as selective LRRK2 inhibitors. WO2012028629A1
  • Reith AD, Bamborough P, Jandu K, et al. GSK257821A: a potent and highly selective 2-arylmethyloxy-5-substituent-N-arylbenzamide LRRK2 kinase inhibitors. Bioorg Med Chem Lett 2012;22:5625-9
  • Hoffmann La Roche. Substituted anilino-carboxamide and/or anilino-alkylcarboxamide pyrimidine as LRRK2 inhibitors. WO2011151360A1
  • Hoffmann La Roche. Substituted pyrazolo aminopyrimidine as LRRK2 inhibitors. WO2012062783A1
  • Hoffmann La Roche. Substituted anilino aminopyrimidine as LRRK2 inhibitors. WO2013079493A1
  • Hoffmann La Roche. Substituted anilino-carboxamide aminopyrimidine as LRRK2 inhibitors. WO2013079494A1
  • Hoffmann La Roche. Substituted anilino and/or 3-pyrido aminopyrimidine as LRRK2 inhibitors. WO2013079495A1
  • Hoffmann La Roche. Substituted and/or fusedanilino aminopyrimidine as LRRK2 inhibitors. WO2013079505A1
  • Hoffmann La Roche. Substituted pyrazolo aminopyrimidine as LRRK2 inhibitors. WO2013164321A1
  • Hoffmann La Roche. Substituted and/or fused pyrazolo aminopyrimidine as LRRK2 inhibitors. WO2013164323A1
  • Ipsen Pharma & Oncodesign. Macrocyclic pyrazolo [1,5-a]pyrimidine as LRRK2 kinase inhibitors. WO2013046029A1
  • Medical Research Council Technology, UK. A method for identifying a compound in modulating a LRRK2 protein kinase activity. WO2008122789A2
  • Medical Research Council Technology, UK. A method for assessing the effect of a compound on LRRK2 in a cell based system. US20110256062A1
  • Medical Research Council Technology, UK. Assay for identification of LRRK2 inhibitors in cell based system. US2011131980A1
  • Medical Research Council Technology, UK. A method of identifying LRRK2 inhibitors. US8206942B2; 2012
  • Medical Research Council Technology, UK. A method for identifying modulators of LRRK2. US8367349B2; 2013
  • Medical Research Council Technology, UK. 3,4-Disubstituted pyrazolo [4,3-c]pyridines as kinase inhibitors more particularly LRRK2. WO2010106333
  • Medical Research Council Technology, UK. 3,4-Disubstituted pyrazolo [4,3-c]pyridines as kinase inhibitors more particularly LRRK2. US20100317646
  • Medical Research Council Technology, UK. Pyrazolopyridines as inhibitors of the kinase LRRK2. WO2011141756
  • Merck Sharp & Dohme Corp, US. Dihydrobenzothiophene derivatives as LRRK2 inhibitors. WO2012058193A1
  • Merck Sharp & Dohme Corp, US. Dihydrobenzothiophene derivatives as LRRK2 inhibitors. WO2012118679A1
  • Novartis AG, Switzerland. Polymorphisms of LRRK2 as biomarker for Alzheimer's disease. WO2007149798A2
  • Novartis AG, Switzerland. Dihydroindole derivatives as LRRK2 inhibitors for Parkinson's disease. WO2009030270A1
  • Anand VS, Reichling LJ, Lipinski K, et al. Investigation of leucine-rich repeat kinase 2: enzymological properties and novel assays. FEBS J 2009;276:466-78
  • Nichols RJ, Dzamko N, Hutti JE, et al. Substrate specificity and inhibitors of LRRK2, a protein kinase mutated in Parkinson's disease. Biochem J 2009;424:47-60
  • Lee BD, Shin JH, VanKampen J, et al. Inhibitors of leucine-rich repeat kinase 2 protect against models of Parkinson's disease. Nat Med 2010;16:998-1000
  • The Johns Hopkins University, USA. LRRK2-mediated neuronal toxicity. WO2011057042A2
  • Troxler T, Greenidge P, Zimmermann K, et al. Discovery of novel indolinone-based, potent, selective and brain penetrant inhibitors of LRRK2. Bioorg Med Chem Lett 2013;23:4085-90
  • Origenis GmbH, Germany. 4,5-Heterofused pyrazolopyridine as kinase inhibitors. WO2012143143A1
  • Origenis GmbH, Germany. Pyrazolo [4,3-d]pyrimidines as kinase inhibitors. WO2012143144A1
  • Origenis GmbH, Germany. 4,5-Heterofused pyrazolopyridine as kinase inhibitors. US20120329780A1
  • Origenis GmbH, Germany. Pyrazolo [4,3-d]pyrimidines as kinase inhibitors. US20120329785A1
  • Southern Methodist University, US. Pyrido [3,2-b]-1,4-oxazin-3-4H-one derivatives as Raf and LRRK2 inhibitors. US20120245347A1
  • Southern Research Institute, US. Triazolopyridazine compounds as LRRK2 inhibitors. WO2013166276A1
  • University of Rochester, US. Bicyclic heteroaryl compounds as mixed lineage kinase and LRRK2 kinase inhibitors. WO2011149950A2
  • Zenobia Therapeutics US. Substituted indolines as selective LRRK2 inhibitors. WO2012178015A2
  • Estrada AA, Chan BK, Baker-Glenn C, et al. Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem 2014;57:921-36

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