Title:
SUBSTITUTED TRICYCLIC HERTEOCYCLIC COMPOUNDS AND USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2017/215600
Kind Code:
A1
Abstract:
Provided are a substituted tricyclic herteocyclic compound of formula I or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, ester or a prodrug thereof, a pharmaceutical composition including the same and uses thereof. The substituted tricyclic herteocyclic compounds and the pharmaceutical compositions comprising the compounds disclosed herein can be used for treating a disorder caused by at least one of cancer and neurodegenerative diseases. Further the compounds and the pharmaceutical compositions comprising the compounds disclosed herein can be also used for preventing or treating a disorder caused by, associated with or accompanied by any abnormal kinase activity.
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Inventors:
XIA YAN (CN)
MCIVER EDWARD GILES (GB)
SONG YANG (CN)
XU YUANYUAN (CN)
ZHU LIN (CN)
CHU CHUNJUN (CN)
WU LING (CN)
LIU MIAO (CN)
BRYANS JUSTIN STEPHEN (GB)
MCIVER EDWARD GILES (GB)
SONG YANG (CN)
XU YUANYUAN (CN)
ZHU LIN (CN)
CHU CHUNJUN (CN)
WU LING (CN)
LIU MIAO (CN)
BRYANS JUSTIN STEPHEN (GB)
Application Number:
PCT/CN2017/088137
Publication Date:
December 21, 2017
Filing Date:
June 13, 2017
Export Citation:
Assignee:
SUZHOU YABAO PHARMACEUTICAL R&D CO LTD (CN)
LIFEARC (GB)
LIFEARC (GB)
International Classes:
C07D491/14; A61K31/4162; A61K31/437; A61P25/00; A61P35/00; C07D243/06; C07D267/04; C07D487/04; C07D498/04; C07D519/00
Domestic Patent References:
| WO2003072550A1 | 2003-09-04 | |||
| WO2013139882A1 | 2013-09-26 | |||
| WO1984003564A1 | 1984-09-13 | |||
| WO2010106333A1 | 2010-09-23 | |||
| WO2012038743A1 | 2012-03-29 |
Foreign References:
| CN102428084A | 2012-04-25 | |||
| CN103261196A | 2013-08-21 |
Other References:
BU X. Y. ET AL.: "Synthesis and cytotoxicity of potential anticancer derivatives of pyrazolo[3, 4, 5-kl]acridine and indolo[2, 3-a]acridine", TETRAHEDRON, vol. 58, 31 December 2002 (2002-12-31), pages 175 - 181, XP004313488, ISSN: 0040-4020
FINGL ET AL., THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 1975, pages 1
A WADEPJ WELLER: "Handbook of Pharmaceutical Excipients", 1994
A. R. GENNARO: "Remington's Pharmaceutical Sciences", 1985, JOHN WILEY AND SONS
BERGE ET AL., J PHARM SCI, vol. 66, 1977, pages 1 - 19
FONZO AWU-CHOU Y-HLU C-SDOESELAAR MSIMONS EJ ET AL.: "A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan", NEUROGENETICS, vol. 7, 2006, pages 133 - 138, XP019385850, DOI: 10.1007/s10048-006-0041-5
LEES AJHARDY JREVESZ T: "Parkinson's disease", LANCET, vol. 373, 2009, pages 2055 - 2066
NALLS MAPANKRATZ NLILL CMDO CBHERNANDEZ DG ET AL.: "Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease", NAT GENET, vol. 46, 2014, pages 989 - 993, XP037030281, DOI: 10.1038/ng.3043
SIMON-SANCHEZ JSCHULTE CBRAS JMSHARMA MGIBBS JR ET AL.: "Genome-wide association study reveals genetic risk underlying Parkinson's disease", NAT GENET, vol. 41, 2009, pages 1308 - 1312, XP002638617, DOI: 10.1038/NG.487
SATAKE WNAKABAYASHI YMIZUTA IHIROTA YITO C ET AL.: "Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease", NAT GENET, vol. 41, 2009, pages 1303 - 1307
RUDENKO IN, COOKSON MR: " Heterogeneity of leucine-rich repeat kinase 2 mutations:genetics, mechanisms and therapeutic implications", NEUROTHERAPEUTICS, vol. 11, 2014, pages 738 - 750
FARRER MJSTONE JTLIN CHDACHSEL JCHULIHAN MM ET AL.: "Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia", PARKINSONISM RELAT DISORD, vol. 13, 2007, pages 89 - 92, XP005893048, DOI: 10.1016/j.parkreldis.2006.12.001
WEST AB, MOORE DJ, BISKUP S, BUGAYENKO A, SMITH WW: "From The Cover:Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 102, 2005, pages 16842 - 16847, XP002437140, DOI: 10.1073/pnas.0507360102
KHAN NLJAIN SLYNCH JMPAVESE NABOU-SLEIMAN P ET AL.: "Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data", BRAIN, 2005
KACHERGUS JMATA IFHULIHAN MTAYLOR JPLINCOLN S ET AL.: "Identification of a Novel LRRK2 Mutation Linked to Autosomal Dominant Parkinsonism: Evidence of a Common Founder across European Populations", THE AMERICAN JOURNAL OF HUMAN GENETICS, vol. 76, 2005, pages 672 - 680, XP002998703, DOI: 10.1086/429256
OZELIUS LJSENTHIL GSAUNDERS-PULLMAN ROHMANN EDELIGTISCH A ET AL.: "LRRK2 G2019S as a Cause of Parkinson's Disease in Ashkenazi Jews", NEW ENGLAND JOURNAL OF MEDICINE, vol. 354, 2006, pages 424 - 425
JALEEL MNICHOLS RJDEAK MCAMPBELL DAVID GGILLARDON F ET AL.: "LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity", BIOCHEMICAL JOURNAL, vol. 405, 2007, pages 307 - 317, XP002494862
ISHIHARA LGIBSON RAWARREN LAMOURI RLYONS K ET AL.: "Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson's disease families", MOVEMENT DISORDERS, vol. 22, 2007, pages 55 - 61
TAN, E. K: "Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease", ANN ACAD MED SINGAPORE, vol. 35, 2006, pages 840 - 842
ROSS OAWU Y-RLEE M-CFUNAYAMA MCHEN M-L ET AL.: "Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease", ANNALS OF NEUROLOGY, vol. 64, 2008, pages 88 - 92, XP071638816, DOI: 10.1002/ana.21405
ROSS OASOTO-ORTOLAZA ALHECKMAN MGAASLY JOABAHUNI N ET AL.: "Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study", THE LANCET NEUROLOGY, vol. 10, 2011, pages 898 - 908
PAISAN-RUIZ CJAIN SEVANS EWGILKS WPSIMON J ET AL.: "Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease", NEURON, vol. 44, 2004, pages 595 - 600, XP002371965, DOI: 10.1016/j.neuron.2004.10.023
ZIMPRICH ABISKUP SLEITNER PLICHTNER PFARRER M ET AL.: "Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology", NEURON, vol. 44, 2004, pages 601 - 607, XP002371964, DOI: 10.1016/j.neuron.2004.11.005
AGALLIU ISAN LUCIANO MMIRELMAN A ET AL.: "Higher frequency of certain cancers in lrrk2 g2019s mutation carriers with parkinson disease: A pooled analysis", JAMA NEUROLOGY, vol. 72, 2015, pages 58 - 65
SINGLETON ABFARRER MJBONIFATI V: "The genetics of Parkinson's disease: Progress and therapeutic implications", MOVEMENT DISORDERS, vol. 28, 2013, pages 14 - 23, XP055192281, DOI: 10.1002/mds.25249
JOSTINS LRIPKE SWEERSMA RKDUERR RHMCGOVERN DP ET AL.: "Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease", NATURE, vol. 491, 2012, pages 119 - 124, XP055484363, DOI: 10.1038/nature11582
MARCINEK PJHA ANSHINDE VSUNDARAMOORTHY ARAJKUMAR R ET AL.: "LRRK2 and RIPK2 Variants in the NOD 2-Mediated Signaling Pathway Are Associated with Susceptibility to Mycobacterium leprae in Indian Populations", PLOS ONE, vol. 8, 2013, pages e73103
MARIN I: "The Parkinson Disease Gene LRRK2: Evolutionary and Structural Insights", MOLECULAR BIOLOGY AND EVOLUTION, vol. 23, 2006, pages 2423 - 2433
RUDENKO INKAGANOVICH AHAUSER DNBEYLINA ACHIA R ET AL.: "The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation", BIOCHEMICAL JOURNAL, vol. 446, 2012, pages 99 - 111
MATA IF, WEDEMEYER WJ, FARRER MJ, TAYLOR JP, GALLO KA: "LRRK2 in Parkinson's disease:protein domains and functional insights", TRENDS IN NEUROSCIENCES, vol. 29, 2006, pages 286 - 293, XP025031251, DOI: 10.1016/j.tins.2006.03.006
TAYLOR JPMATA IFFARRER MJ: "RRK2: a common pathway for parkinsonism, pathogenesis and prevention?", TRENDS IN MOLECULAR MEDICINE, vol. 12, 2006, pages 76 - 82, XP028058701, DOI: 10.1016/j.molmed.2005.12.004
GREGGIO EJAIN SKINGSBURY ABANDOPADHYAY RLEWIS P ET AL.: "Kinase activity is required for the toxic effects of mutant LRRK2/dardarin", NEUROBIOLOGY OF DISEASE, vol. 23, 2006, pages 329 - 341
HEO HYPARK J-MKIM C-HHAN BSKIM K-S ET AL.: "LRRK2 enhances oxidative stress-induced neurotoxicity via its kinase activity", EXPERIMENTAL CELL RESEARCH, vol. 316, 2010, pages 649 - 656, XP026879373
REINHARDT PSCHMID BBURBULLA LENA FSCHONDORF DAVID CWAGNER L ET AL.: "Genetic Correction of a LRRK2 Mutation in Human iPSCs Links Parkinsonian Neurodegeneration to ERK-Dependent Changes in Gene Expression", CELL STEM CELL, vol. 12, 2013, pages 354 - 367, XP055343917, DOI: 10.1016/j.stem.2013.01.008
SANDERS LH, LAGANIERE J, COOPER O, MAK SK, VU BJ: "LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients:Reversal by gene correction", NEUROBIOLOGY OF DISEASE, vol. 62, 2014, pages 381 - 386, XP055371359, DOI: 10.1016/j.nbd.2013.10.013
MANZONI CLEWIS PA: "Dysfunction of the autophagy/lysosomal degradation pathway is a shared feature of the genetic synucleinopathies", THE FASEB JOURNAL, vol. 27, 2013, pages 3424 - 3429
ORENSTEIN SJKUO S-HTASSET IARIAS EKOGA H ET AL.: "Interplay of LRRK2 with chaperone-mediated autophagy", NAT NEUROSCI, vol. 16, 2013, pages 394 - 406
MANZONI CMAMAIS ADIHANICH SABETI RSOUTAR MPM ET AL.: "Inhibition of LRRK2 kinase activity stimulates macroautophagy", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - MOLECULAR CELL RESEARCH, vol. 1833, 2013, pages 2900 - 2910, XP028773978, DOI: 10.1016/j.bbamcr.2013.07.020
SWAN MSAUNDERS-PULLMAN R: "The Association Between β-Glucocerebrosidase Mutations and Parkinsonism", CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS, vol. 13, 2013, pages 1 - 10, XP037594765, DOI: 10.1007/s11910-013-0368-x
LI LZHANG XLE W: "Autophagy Dysfunction in Alzheimer's Disease", NEURODEGENERATIVE DISEASES, vol. 7, 2010, pages 265 - 271
NIXON RA: "The role of autophagy in neurodegenerative disease", NAT MED, vol. 19, 2013, pages 983 - 997
WESTBROEK WGUSTAFSON AMSIDRANSKY E: "Exploring the link between glucocerebrosidase mutations and parkinsonism", TRENDS IN MOLECULAR MEDICINE, vol. 17, 2011, pages 485 - 493, XP028273996, DOI: 10.1016/j.molmed.2011.05.003
REDDY JVGANLEY IGPFEFFER SR: "Clues to Neuro-Degeneration in Niemann-Pick Type C Disease from Global Gene Expression Profiling", PLOS ONE, vol. 1, 2006, pages e19, XP093078653, DOI: 10.1371/journal.pone.0000019
KAWAKAMI FYABATA TOHTA EMAEKAWA TSHIMADA N ET AL.: "LRRK2 Phosphorylates Tubulin-Associated Tau but Not the Free Molecule: LRRK2-Mediated Regulation of the Tau-Tubulin Association and Neurite Outgrowth", PLOS ONE, vol. 7, 2012, pages e30834
TAYMANS J-MCOOKSON MR: "Mechanisms in dominant parkinsonism: The toxic triangle of LRRK2, a-synuclein, and", BIOESSAYS, vol. 32, 2010, pages 227 - 235, XP071525477, DOI: 10.1002/bies.200900163
BAILEY RMCOVY JPMELROSE HLROUSSEAU LWATKINSON R ET AL.: "LRRK2 phosphorylates novel tau epitopes and promotes tauopathy", ACTA NEUROPATHOLOGICA, vol. 126, 2013, pages 809 - 827
LI YLIU WOO TFWANG LTANG Y ET AL.: "Mutant LRRK2R1441G BAC transgenic mice recapitulate cardinal features of Parkinson's disease", NAT NEUROSCI, vol. 12, 2009, pages 826 - 828
GOEDERT MJAKES R: "Mutations causing neurodegenerative tauopathies", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - MOLECULAR BASIS OF DISEASE, vol. 1739, 2005, pages 240 - 250, XP025329106, DOI: 10.1016/j.bbadis.2004.08.007
ROTHMAN RBBLOUGH BEBAUMANN MH: "Progress in Brain Research", 2008, ELSEVIER, article "Dopamine/serotonin releasers as medications for stimulant addictions", pages: 385 - 406
BRAND AHPERRIMON N: "Targeted gene expression as a means of altering cell fates and generating dominant phenotypes", DEVELOPMENT, vol. 118, 1993, pages 401 - 415
LIU ZWANG XYU YLI XWANG T ET AL.: "A Drosophila model for LRRK2-linked parkinsonism", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 105, 2008, pages 2693 - 2698, XP055368622, DOI: 10.1073/pnas.0708452105
LIU ZHAMAMICHI SDAE LEE BYANG DRAY A ET AL.: "Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models", HUMAN MOLECULAR GENETICS, vol. 20, 2011, pages 3933 - 3942, XP055370577, DOI: 10.1093/hmg/ddr312
See also references of EP 3472171A4
FINGL ET AL., THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 1975, pages 1
A WADEPJ WELLER: "Handbook of Pharmaceutical Excipients", 1994
A. R. GENNARO: "Remington's Pharmaceutical Sciences", 1985, JOHN WILEY AND SONS
BERGE ET AL., J PHARM SCI, vol. 66, 1977, pages 1 - 19
FONZO AWU-CHOU Y-HLU C-SDOESELAAR MSIMONS EJ ET AL.: "A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan", NEUROGENETICS, vol. 7, 2006, pages 133 - 138, XP019385850, DOI: 10.1007/s10048-006-0041-5
LEES AJHARDY JREVESZ T: "Parkinson's disease", LANCET, vol. 373, 2009, pages 2055 - 2066
NALLS MAPANKRATZ NLILL CMDO CBHERNANDEZ DG ET AL.: "Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease", NAT GENET, vol. 46, 2014, pages 989 - 993, XP037030281, DOI: 10.1038/ng.3043
SIMON-SANCHEZ JSCHULTE CBRAS JMSHARMA MGIBBS JR ET AL.: "Genome-wide association study reveals genetic risk underlying Parkinson's disease", NAT GENET, vol. 41, 2009, pages 1308 - 1312, XP002638617, DOI: 10.1038/NG.487
SATAKE WNAKABAYASHI YMIZUTA IHIROTA YITO C ET AL.: "Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease", NAT GENET, vol. 41, 2009, pages 1303 - 1307
RUDENKO IN, COOKSON MR: " Heterogeneity of leucine-rich repeat kinase 2 mutations:genetics, mechanisms and therapeutic implications", NEUROTHERAPEUTICS, vol. 11, 2014, pages 738 - 750
FARRER MJSTONE JTLIN CHDACHSEL JCHULIHAN MM ET AL.: "Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia", PARKINSONISM RELAT DISORD, vol. 13, 2007, pages 89 - 92, XP005893048, DOI: 10.1016/j.parkreldis.2006.12.001
WEST AB, MOORE DJ, BISKUP S, BUGAYENKO A, SMITH WW: "From The Cover:Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 102, 2005, pages 16842 - 16847, XP002437140, DOI: 10.1073/pnas.0507360102
KHAN NLJAIN SLYNCH JMPAVESE NABOU-SLEIMAN P ET AL.: "Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data", BRAIN, 2005
KACHERGUS JMATA IFHULIHAN MTAYLOR JPLINCOLN S ET AL.: "Identification of a Novel LRRK2 Mutation Linked to Autosomal Dominant Parkinsonism: Evidence of a Common Founder across European Populations", THE AMERICAN JOURNAL OF HUMAN GENETICS, vol. 76, 2005, pages 672 - 680, XP002998703, DOI: 10.1086/429256
OZELIUS LJSENTHIL GSAUNDERS-PULLMAN ROHMANN EDELIGTISCH A ET AL.: "LRRK2 G2019S as a Cause of Parkinson's Disease in Ashkenazi Jews", NEW ENGLAND JOURNAL OF MEDICINE, vol. 354, 2006, pages 424 - 425
JALEEL MNICHOLS RJDEAK MCAMPBELL DAVID GGILLARDON F ET AL.: "LRRK2 phosphorylates moesin at threonine-558: characterization of how Parkinson's disease mutants affect kinase activity", BIOCHEMICAL JOURNAL, vol. 405, 2007, pages 307 - 317, XP002494862
ISHIHARA LGIBSON RAWARREN LAMOURI RLYONS K ET AL.: "Screening for Lrrk2 G2019S and clinical comparison of Tunisian and North American Caucasian Parkinson's disease families", MOVEMENT DISORDERS, vol. 22, 2007, pages 55 - 61
TAN, E. K: "Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease", ANN ACAD MED SINGAPORE, vol. 35, 2006, pages 840 - 842
ROSS OAWU Y-RLEE M-CFUNAYAMA MCHEN M-L ET AL.: "Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease", ANNALS OF NEUROLOGY, vol. 64, 2008, pages 88 - 92, XP071638816, DOI: 10.1002/ana.21405
ROSS OASOTO-ORTOLAZA ALHECKMAN MGAASLY JOABAHUNI N ET AL.: "Association of LRRK2 exonic variants with susceptibility to Parkinson's disease: a case-control study", THE LANCET NEUROLOGY, vol. 10, 2011, pages 898 - 908
PAISAN-RUIZ CJAIN SEVANS EWGILKS WPSIMON J ET AL.: "Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease", NEURON, vol. 44, 2004, pages 595 - 600, XP002371965, DOI: 10.1016/j.neuron.2004.10.023
ZIMPRICH ABISKUP SLEITNER PLICHTNER PFARRER M ET AL.: "Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology", NEURON, vol. 44, 2004, pages 601 - 607, XP002371964, DOI: 10.1016/j.neuron.2004.11.005
AGALLIU ISAN LUCIANO MMIRELMAN A ET AL.: "Higher frequency of certain cancers in lrrk2 g2019s mutation carriers with parkinson disease: A pooled analysis", JAMA NEUROLOGY, vol. 72, 2015, pages 58 - 65
SINGLETON ABFARRER MJBONIFATI V: "The genetics of Parkinson's disease: Progress and therapeutic implications", MOVEMENT DISORDERS, vol. 28, 2013, pages 14 - 23, XP055192281, DOI: 10.1002/mds.25249
JOSTINS LRIPKE SWEERSMA RKDUERR RHMCGOVERN DP ET AL.: "Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease", NATURE, vol. 491, 2012, pages 119 - 124, XP055484363, DOI: 10.1038/nature11582
MARCINEK PJHA ANSHINDE VSUNDARAMOORTHY ARAJKUMAR R ET AL.: "LRRK2 and RIPK2 Variants in the NOD 2-Mediated Signaling Pathway Are Associated with Susceptibility to Mycobacterium leprae in Indian Populations", PLOS ONE, vol. 8, 2013, pages e73103
MARIN I: "The Parkinson Disease Gene LRRK2: Evolutionary and Structural Insights", MOLECULAR BIOLOGY AND EVOLUTION, vol. 23, 2006, pages 2423 - 2433
RUDENKO INKAGANOVICH AHAUSER DNBEYLINA ACHIA R ET AL.: "The G2385R variant of leucine-rich repeat kinase 2 associated with Parkinson's disease is a partial loss-of-function mutation", BIOCHEMICAL JOURNAL, vol. 446, 2012, pages 99 - 111
MATA IF, WEDEMEYER WJ, FARRER MJ, TAYLOR JP, GALLO KA: "LRRK2 in Parkinson's disease:protein domains and functional insights", TRENDS IN NEUROSCIENCES, vol. 29, 2006, pages 286 - 293, XP025031251, DOI: 10.1016/j.tins.2006.03.006
TAYLOR JPMATA IFFARRER MJ: "RRK2: a common pathway for parkinsonism, pathogenesis and prevention?", TRENDS IN MOLECULAR MEDICINE, vol. 12, 2006, pages 76 - 82, XP028058701, DOI: 10.1016/j.molmed.2005.12.004
GREGGIO EJAIN SKINGSBURY ABANDOPADHYAY RLEWIS P ET AL.: "Kinase activity is required for the toxic effects of mutant LRRK2/dardarin", NEUROBIOLOGY OF DISEASE, vol. 23, 2006, pages 329 - 341
HEO HYPARK J-MKIM C-HHAN BSKIM K-S ET AL.: "LRRK2 enhances oxidative stress-induced neurotoxicity via its kinase activity", EXPERIMENTAL CELL RESEARCH, vol. 316, 2010, pages 649 - 656, XP026879373
REINHARDT PSCHMID BBURBULLA LENA FSCHONDORF DAVID CWAGNER L ET AL.: "Genetic Correction of a LRRK2 Mutation in Human iPSCs Links Parkinsonian Neurodegeneration to ERK-Dependent Changes in Gene Expression", CELL STEM CELL, vol. 12, 2013, pages 354 - 367, XP055343917, DOI: 10.1016/j.stem.2013.01.008
SANDERS LH, LAGANIERE J, COOPER O, MAK SK, VU BJ: "LRRK2 mutations cause mitochondrial DNA damage in iPSC-derived neural cells from Parkinson's disease patients:Reversal by gene correction", NEUROBIOLOGY OF DISEASE, vol. 62, 2014, pages 381 - 386, XP055371359, DOI: 10.1016/j.nbd.2013.10.013
MANZONI CLEWIS PA: "Dysfunction of the autophagy/lysosomal degradation pathway is a shared feature of the genetic synucleinopathies", THE FASEB JOURNAL, vol. 27, 2013, pages 3424 - 3429
ORENSTEIN SJKUO S-HTASSET IARIAS EKOGA H ET AL.: "Interplay of LRRK2 with chaperone-mediated autophagy", NAT NEUROSCI, vol. 16, 2013, pages 394 - 406
MANZONI CMAMAIS ADIHANICH SABETI RSOUTAR MPM ET AL.: "Inhibition of LRRK2 kinase activity stimulates macroautophagy", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - MOLECULAR CELL RESEARCH, vol. 1833, 2013, pages 2900 - 2910, XP028773978, DOI: 10.1016/j.bbamcr.2013.07.020
SWAN MSAUNDERS-PULLMAN R: "The Association Between β-Glucocerebrosidase Mutations and Parkinsonism", CURRENT NEUROLOGY AND NEUROSCIENCE REPORTS, vol. 13, 2013, pages 1 - 10, XP037594765, DOI: 10.1007/s11910-013-0368-x
LI LZHANG XLE W: "Autophagy Dysfunction in Alzheimer's Disease", NEURODEGENERATIVE DISEASES, vol. 7, 2010, pages 265 - 271
NIXON RA: "The role of autophagy in neurodegenerative disease", NAT MED, vol. 19, 2013, pages 983 - 997
WESTBROEK WGUSTAFSON AMSIDRANSKY E: "Exploring the link between glucocerebrosidase mutations and parkinsonism", TRENDS IN MOLECULAR MEDICINE, vol. 17, 2011, pages 485 - 493, XP028273996, DOI: 10.1016/j.molmed.2011.05.003
REDDY JVGANLEY IGPFEFFER SR: "Clues to Neuro-Degeneration in Niemann-Pick Type C Disease from Global Gene Expression Profiling", PLOS ONE, vol. 1, 2006, pages e19, XP093078653, DOI: 10.1371/journal.pone.0000019
KAWAKAMI FYABATA TOHTA EMAEKAWA TSHIMADA N ET AL.: "LRRK2 Phosphorylates Tubulin-Associated Tau but Not the Free Molecule: LRRK2-Mediated Regulation of the Tau-Tubulin Association and Neurite Outgrowth", PLOS ONE, vol. 7, 2012, pages e30834
TAYMANS J-MCOOKSON MR: "Mechanisms in dominant parkinsonism: The toxic triangle of LRRK2, a-synuclein, and", BIOESSAYS, vol. 32, 2010, pages 227 - 235, XP071525477, DOI: 10.1002/bies.200900163
BAILEY RMCOVY JPMELROSE HLROUSSEAU LWATKINSON R ET AL.: "LRRK2 phosphorylates novel tau epitopes and promotes tauopathy", ACTA NEUROPATHOLOGICA, vol. 126, 2013, pages 809 - 827
LI YLIU WOO TFWANG LTANG Y ET AL.: "Mutant LRRK2R1441G BAC transgenic mice recapitulate cardinal features of Parkinson's disease", NAT NEUROSCI, vol. 12, 2009, pages 826 - 828
GOEDERT MJAKES R: "Mutations causing neurodegenerative tauopathies", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - MOLECULAR BASIS OF DISEASE, vol. 1739, 2005, pages 240 - 250, XP025329106, DOI: 10.1016/j.bbadis.2004.08.007
ROTHMAN RBBLOUGH BEBAUMANN MH: "Progress in Brain Research", 2008, ELSEVIER, article "Dopamine/serotonin releasers as medications for stimulant addictions", pages: 385 - 406
BRAND AHPERRIMON N: "Targeted gene expression as a means of altering cell fates and generating dominant phenotypes", DEVELOPMENT, vol. 118, 1993, pages 401 - 415
LIU ZWANG XYU YLI XWANG T ET AL.: "A Drosophila model for LRRK2-linked parkinsonism", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 105, 2008, pages 2693 - 2698, XP055368622, DOI: 10.1073/pnas.0708452105
LIU ZHAMAMICHI SDAE LEE BYANG DRAY A ET AL.: "Inhibitors of LRRK2 kinase attenuate neurodegeneration and Parkinson-like phenotypes in Caenorhabditis elegans and Drosophila Parkinson's disease models", HUMAN MOLECULAR GENETICS, vol. 20, 2011, pages 3933 - 3942, XP055370577, DOI: 10.1093/hmg/ddr312
See also references of EP 3472171A4
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TSINGYIHUA INTELLECTUAL PROPERTY LLC (CN)
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