Title:
SERINE DERIVATIVE COMPOUND FOR PREVENTING OR TREATING CENTRAL NERVOUS SYSTEM DISEASES
Document Type and Number:
WIPO Patent Application WO/2020/145584
Kind Code:
A1
Abstract:
The present invention relates to a novel serine derivative compound having improved blood-brain barrier (BBB) permeability, and a use of same, and more specifically, to a novel serine derivative compound having further improved BBB permeability compared to L-serine, and a pharmaceutical composition comprising the compound as an effective compound for preventing or treating/alleviating central nervous system diseases, such as cognitive disorders, intellectual disabilities, microcephaly, epilepsy, neurodevelopmental disorders, dementia, autism spectrum disorders, Down syndrome, Rett syndrome, fragile X syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A compound of chemical formula (I) or a pharmaceutically acceptable salt thereof as an effective component for the pharmaceutical composition of the present invention for preventing or treating central nervous system diseases exhibits significantly improved BBB permeability compared to L-serine, and activates the propagation of neurons, and through the neuroprotective effect that inhibits oxidative stress-induced mitochondrial membrane potential disruption and/or endoplasmic reticulum stress-induced apoptotic neuronal cell death, exhibits desirable effects in the prevention, treatment, and alleviation of central nervous system diseases, such as cognitive disorders, intellectual disabilities, microcephaly, epilepsy, neurodevelopmental disorders, dementia, autism spectrum disorders, Down syndrome, Rett syndrome, fragile X syndrome, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Thus, the compound is an extremely useful invention in the drug industry, food industry, and livestock industry.
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Inventors:
KIM YOUNG HO (KR)
WHANG SU-KYEONG (KR)
JUN DO YOUN (KR)
JO YOUNG KYOUNG (KR)
LEE MIN YONG (KR)
WHANG SU-KYEONG (KR)
JUN DO YOUN (KR)
JO YOUNG KYOUNG (KR)
LEE MIN YONG (KR)
Application Number:
PCT/KR2020/000154
Publication Date:
July 16, 2020
Filing Date:
January 03, 2020
Export Citation:
Assignee:
ASTROGEN CO LTD (KR)
International Classes:
C07C271/02; A61K31/27; A61K38/08; A61P25/00; C07K1/04; C07K5/10
Domestic Patent References:
| WO2004000297A1 | 2003-12-31 |
Foreign References:
| US20140212893A1 | 2014-07-31 | |||
| KR20010022323A | 2001-03-15 | |||
| JPH10245369A | 1998-09-14 |
Other References:
KUBOTA, S.: "Conformation of Sequential Polypeptides of (Lysi-Leuj), (Lysi-Serj), and (Lys-Gly) in Sodium Dodecyl Sulfate Solution", BIOPOLYMERS, vol. 22, no. 10, October 1983 (1983-10-01), pages 2237 - 2252, XP055724789
BHAT AHDAR KBANEES SZARGAR MAMASOOD ASOFI MAGANIE SA: "Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight", BIOMED PHARMACOTHER, vol. 74, 2015, pages 101 - 110
COZZOLINO MCARRI MT: "Mitochondrial dysfunction in ALS", PROG NEUROBIOL, vol. 97, no. 2, 2012, pages 54 - 66, XP028917037, DOI: 10.1016/j.pneurobio.2011.06.003
DE KONING TJDURAN MVAN MALDERGEM LPINEDA MDORLAND LGOOSKENS RJAEKEN JPOLL-THE BT: "Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids", J INHERIT METAB DIS, vol. 25, no. 2, 2002, pages 119 - 125
DE KONING TJSNELL KDURAN MBERGER RPOLL-THE BTSURTEES R: "L-serine in disease and development", BIOCHEMJ, vol. 371, 2003, pages 653 - 661
DOYLE KMKENNEDY DGORMAN AMGUPTA SHEALY SJSAMALI A: "Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders", J CELLMOLMED, vol. 15, no. 10, 2011, pages 2025 - 2039
DRANKA BPHILL BGDARLEY-USMAR VM: "Mitochondrial reserve capacity in endothelial cells: The impact of nitric oxide and reactive oxygen species", FREE RADIC BIOL MED, vol. 48, no. 7, 2010, pages 905 - 914, XP026925851, DOI: 10.1016/j.freeradbiomed.2010.01.015
DUNLOP RAPOWELL JTMETCALF JSGUILLEMIN GJCOX PA: "L-Serine-mediated neuroprotection includes the upregulation of the ER stress chaperone protein disulfide isomerase (PDI", NEUROTOX RES, vol. 33, no. 1, 2018, pages 113 - 122, XP036379751, DOI: 10.1007/s12640-017-9817-7
EL-HATTAB AW: "Serine biosynthesis and transport defects", MOL GENET METAB, vol. 118, no. 3, 2016, pages 153 - 159, XP029617296, DOI: 10.1016/j.ymgme.2016.04.010
FRANCO-IBORRA SVILA MPERIER C: "Mitochondrial quality control in neurodegenerative diseases: Focus on Parkinson's disease and Huntington's disease", FRONT NEUROSCI, vol. 12, 2018, pages 342
FURUYA STABATA TMITOMA JYAMADA KYAMASAKI MMAKINO AYAMAMOTO TWATANABE MKANO MHIRABAYASHI Y: "L-serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons", PROC NATL AEAD SCI USA, vol. 97, no. 21, 2000, pages 11528 - 11533
LENCH AMMASSEY PVPOLLEGIONI LWOODHALL GLJONES RS: "Astroglial d-serine is the endogenous co-agonist at the presynaptic NMDA receptor in rat entorhinal cortex", NEUROPHARMACOLOGY, vol. 83, 2014, pages 118 - 127
METCALF JSDUNLOP RAPOWELL JTBANACK SACOX PA: "L-Serine: a Naturally-occurring amino acid with therapeutic potential", NEUROTOX RES, vol. 33, no. 1, 2018, pages 213 - 221, XP036379750, DOI: 10.1007/s12640-017-9814-x
NI HMWILLIAMS JADING WX: "Mitochondrial dynamics and mitochondrial quality control", REDOX BIOL, vol. 4, 2015, pages 6 - 13
OGAWA SKITAO YHORI O: "Ischemia-induced neuronal cell death and stress response", ANTIOXID REDOX SIGNAL, vol. 9, no. 5, 2007, pages 573 - 587
PINEDA MVILASECA MAARTUCH RSANTOS SGARCIA GONZALEZ MMARACIL AVAN SCHAFTINGEN EJAEKEN J: "3-phosphoglycerate dehydrogenase deficiency in a patient with West syndrome", DEV MED CHILD NEUROL, vol. 42, no. 9, 2000, pages 629 - 633
SMITH QR: "Transport of glutamate and other amino acids at the blood-brain barrier", J NUTR., vol. 130, 2000, pages 1016S - 1022S, XP009501113, DOI: 10.1093/jn/130.4.1016S
TABATABAIE LKLOMP LWRUBIO-GOZALBO MESPAAPEN LJHAAGEN AADORLAND LDE KONING TJ: "Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency", J INHERIT METAB DIS, vol. 34, no. 1, 2011, pages 181 - 184, XP019876552, DOI: 10.1007/s10545-010-9249-5
VALENTI DDE BAN LDE FILIPPIS BHENRION-CAUDE AVACCA RA: "Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: an overview of Down syndrome, autism, Fragile X and Rett syndrome", NEUROSCI BIOBEHAV REV, vol. 46, 2014, pages 202 - 217
WANG XWANG WLI LPERRY GLEE HGZHU X: "Oxidative stress and mitochondrial dysfunction in Alzheimer's disease", BIOCHIM BIOPHYS ACTA, vol. 1842, no. 8, 2014, pages 1240 - 1247, XP028873353, DOI: 10.1016/j.bbadis.2013.10.015
WOLOSKER HPANIZZUTTI RDE MIRANDA J: "Neurobiology through the looking-glass: D-serine as a new glial-derived transmitter", NEUROCHEM INT, vol. 41, no. 5, 2002, pages 327 - 332
YOULE RJVAN DER BLIEK AM: "Mitochondrial fission, fusion, and stress", SCIENCE, vol. 337, no. 6098, 2012, pages 1062 - 1065
STAHLWERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2002, WILEY-VCH
See also references of EP 3822255A4
BHAT AHDAR KBANEES SZARGAR MAMASOOD ASOFI MAGANIE SA: "Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight", BIOMED PHARMACOTHER, vol. 74, 2015, pages 101 - 110
COZZOLINO MCARRI MT: "Mitochondrial dysfunction in ALS", PROG NEUROBIOL, vol. 97, no. 2, 2012, pages 54 - 66, XP028917037, DOI: 10.1016/j.pneurobio.2011.06.003
DE KONING TJDURAN MVAN MALDERGEM LPINEDA MDORLAND LGOOSKENS RJAEKEN JPOLL-THE BT: "Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids", J INHERIT METAB DIS, vol. 25, no. 2, 2002, pages 119 - 125
DE KONING TJSNELL KDURAN MBERGER RPOLL-THE BTSURTEES R: "L-serine in disease and development", BIOCHEMJ, vol. 371, 2003, pages 653 - 661
DOYLE KMKENNEDY DGORMAN AMGUPTA SHEALY SJSAMALI A: "Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders", J CELLMOLMED, vol. 15, no. 10, 2011, pages 2025 - 2039
DRANKA BPHILL BGDARLEY-USMAR VM: "Mitochondrial reserve capacity in endothelial cells: The impact of nitric oxide and reactive oxygen species", FREE RADIC BIOL MED, vol. 48, no. 7, 2010, pages 905 - 914, XP026925851, DOI: 10.1016/j.freeradbiomed.2010.01.015
DUNLOP RAPOWELL JTMETCALF JSGUILLEMIN GJCOX PA: "L-Serine-mediated neuroprotection includes the upregulation of the ER stress chaperone protein disulfide isomerase (PDI", NEUROTOX RES, vol. 33, no. 1, 2018, pages 113 - 122, XP036379751, DOI: 10.1007/s12640-017-9817-7
EL-HATTAB AW: "Serine biosynthesis and transport defects", MOL GENET METAB, vol. 118, no. 3, 2016, pages 153 - 159, XP029617296, DOI: 10.1016/j.ymgme.2016.04.010
FRANCO-IBORRA SVILA MPERIER C: "Mitochondrial quality control in neurodegenerative diseases: Focus on Parkinson's disease and Huntington's disease", FRONT NEUROSCI, vol. 12, 2018, pages 342
FURUYA STABATA TMITOMA JYAMADA KYAMASAKI MMAKINO AYAMAMOTO TWATANABE MKANO MHIRABAYASHI Y: "L-serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons", PROC NATL AEAD SCI USA, vol. 97, no. 21, 2000, pages 11528 - 11533
LENCH AMMASSEY PVPOLLEGIONI LWOODHALL GLJONES RS: "Astroglial d-serine is the endogenous co-agonist at the presynaptic NMDA receptor in rat entorhinal cortex", NEUROPHARMACOLOGY, vol. 83, 2014, pages 118 - 127
METCALF JSDUNLOP RAPOWELL JTBANACK SACOX PA: "L-Serine: a Naturally-occurring amino acid with therapeutic potential", NEUROTOX RES, vol. 33, no. 1, 2018, pages 213 - 221, XP036379750, DOI: 10.1007/s12640-017-9814-x
NI HMWILLIAMS JADING WX: "Mitochondrial dynamics and mitochondrial quality control", REDOX BIOL, vol. 4, 2015, pages 6 - 13
OGAWA SKITAO YHORI O: "Ischemia-induced neuronal cell death and stress response", ANTIOXID REDOX SIGNAL, vol. 9, no. 5, 2007, pages 573 - 587
PINEDA MVILASECA MAARTUCH RSANTOS SGARCIA GONZALEZ MMARACIL AVAN SCHAFTINGEN EJAEKEN J: "3-phosphoglycerate dehydrogenase deficiency in a patient with West syndrome", DEV MED CHILD NEUROL, vol. 42, no. 9, 2000, pages 629 - 633
SMITH QR: "Transport of glutamate and other amino acids at the blood-brain barrier", J NUTR., vol. 130, 2000, pages 1016S - 1022S, XP009501113, DOI: 10.1093/jn/130.4.1016S
TABATABAIE LKLOMP LWRUBIO-GOZALBO MESPAAPEN LJHAAGEN AADORLAND LDE KONING TJ: "Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency", J INHERIT METAB DIS, vol. 34, no. 1, 2011, pages 181 - 184, XP019876552, DOI: 10.1007/s10545-010-9249-5
VALENTI DDE BAN LDE FILIPPIS BHENRION-CAUDE AVACCA RA: "Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: an overview of Down syndrome, autism, Fragile X and Rett syndrome", NEUROSCI BIOBEHAV REV, vol. 46, 2014, pages 202 - 217
WANG XWANG WLI LPERRY GLEE HGZHU X: "Oxidative stress and mitochondrial dysfunction in Alzheimer's disease", BIOCHIM BIOPHYS ACTA, vol. 1842, no. 8, 2014, pages 1240 - 1247, XP028873353, DOI: 10.1016/j.bbadis.2013.10.015
WOLOSKER HPANIZZUTTI RDE MIRANDA J: "Neurobiology through the looking-glass: D-serine as a new glial-derived transmitter", NEUROCHEM INT, vol. 41, no. 5, 2002, pages 327 - 332
YOULE RJVAN DER BLIEK AM: "Mitochondrial fission, fusion, and stress", SCIENCE, vol. 337, no. 6098, 2012, pages 1062 - 1065
STAHLWERMUTH: "Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2002, WILEY-VCH
See also references of EP 3822255A4
Attorney, Agent or Firm:
SUH, Jang-Chan et al. (KR)
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