CN113811304A - 2-苯基-6-(1h-咪唑-1-基)喹唑啉用于治疗神经退行性疾病,优选阿尔茨海默病的用途 - Google Patents
2-苯基-6-(1h-咪唑-1-基)喹唑啉用于治疗神经退行性疾病,优选阿尔茨海默病的用途 Download PDFInfo
- Publication number
- CN113811304A CN113811304A CN202080034767.XA CN202080034767A CN113811304A CN 113811304 A CN113811304 A CN 113811304A CN 202080034767 A CN202080034767 A CN 202080034767A CN 113811304 A CN113811304 A CN 113811304A
- Authority
- CN
- China
- Prior art keywords
- disease
- alzheimer
- dementia
- imidazol
- quinazoline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000024827 Alzheimer disease Diseases 0.000 title claims abstract description 55
- 230000004770 neurodegeneration Effects 0.000 title claims abstract description 52
- 208000015122 neurodegenerative disease Diseases 0.000 title claims abstract description 45
- 238000011282 treatment Methods 0.000 title claims abstract description 30
- CSZGXYBGYFNSCO-UHFFFAOYSA-N 6-imidazol-1-yl-2-phenylquinazoline Chemical compound C1=NC=CN1C1=CC=C(N=C(N=C2)C=3C=CC=CC=3)C2=C1 CSZGXYBGYFNSCO-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims abstract description 13
- 201000011240 Frontotemporal dementia Diseases 0.000 claims abstract description 12
- 208000023105 Huntington disease Diseases 0.000 claims abstract description 12
- 201000002832 Lewy body dementia Diseases 0.000 claims abstract description 12
- 208000024777 Prion disease Diseases 0.000 claims abstract description 12
- 206010067889 Dementia with Lewy bodies Diseases 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims description 14
- 206010012289 Dementia Diseases 0.000 claims description 10
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- 239000000544 cholinesterase inhibitor Substances 0.000 claims description 4
- 229940044551 receptor antagonist Drugs 0.000 claims description 4
- 239000002464 receptor antagonist Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 claims description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 3
- 229930195712 glutamate Natural products 0.000 claims description 3
- 229940049906 glutamate Drugs 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 229940022663 acetate Drugs 0.000 claims description 2
- 229940072107 ascorbate Drugs 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229940009098 aspartate Drugs 0.000 claims description 2
- 229940050390 benzoate Drugs 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 229940001468 citrate Drugs 0.000 claims description 2
- 229940009662 edetate Drugs 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 2
- 229960001860 salicylate Drugs 0.000 claims description 2
- 229940086735 succinate Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 206010065040 AIDS dementia complex Diseases 0.000 abstract description 5
- 208000010877 cognitive disease Diseases 0.000 abstract description 3
- 208000028698 Cognitive impairment Diseases 0.000 abstract 1
- 210000004556 brain Anatomy 0.000 description 28
- 241000700159 Rattus Species 0.000 description 26
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 25
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 25
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 25
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 25
- 229960002646 scopolamine Drugs 0.000 description 25
- 102000014458 Protein Kinase C-epsilon Human genes 0.000 description 24
- 108010078137 Protein Kinase C-epsilon Proteins 0.000 description 24
- 238000012360 testing method Methods 0.000 description 24
- 230000000694 effects Effects 0.000 description 22
- 238000000034 method Methods 0.000 description 19
- 230000005945 translocation Effects 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 210000002569 neuron Anatomy 0.000 description 15
- 230000014509 gene expression Effects 0.000 description 14
- 230000004913 activation Effects 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 102000003923 Protein Kinase C Human genes 0.000 description 11
- 108090000315 Protein Kinase C Proteins 0.000 description 11
- 239000003446 ligand Substances 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 210000003169 central nervous system Anatomy 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 238000012549 training Methods 0.000 description 9
- 102400000967 Bradykinin Human genes 0.000 description 8
- 101800004538 Bradykinin Proteins 0.000 description 8
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 8
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 8
- 210000000274 microglia Anatomy 0.000 description 8
- 210000002381 plasma Anatomy 0.000 description 8
- 230000009261 transgenic effect Effects 0.000 description 8
- 238000011818 5xFAD mouse Methods 0.000 description 7
- 210000000170 cell membrane Anatomy 0.000 description 7
- HPMRFMKYPGXPEP-UHFFFAOYSA-N idazoxan Chemical compound N1CCN=C1C1OC2=CC=CC=C2OC1 HPMRFMKYPGXPEP-UHFFFAOYSA-N 0.000 description 7
- 229950001476 idazoxan Drugs 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 206010027175 memory impairment Diseases 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 210000001130 astrocyte Anatomy 0.000 description 6
- 230000001684 chronic effect Effects 0.000 description 6
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 230000006724 microglial activation Effects 0.000 description 6
- 238000011533 pre-incubation Methods 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 208000000044 Amnesia Diseases 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 102000009032 Imidazoline Receptors Human genes 0.000 description 5
- 108010049134 Imidazoline Receptors Proteins 0.000 description 5
- 102000003777 Interleukin-1 beta Human genes 0.000 description 5
- 108090000193 Interleukin-1 beta Proteins 0.000 description 5
- 208000026139 Memory disease Diseases 0.000 description 5
- 230000002757 inflammatory effect Effects 0.000 description 5
- 230000003447 ipsilateral effect Effects 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 5
- 230000000324 neuroprotective effect Effects 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 230000002093 peripheral effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 210000000278 spinal cord Anatomy 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- QYPPJABKJHAVHS-UHFFFAOYSA-N Agmatine Natural products NCCCCNC(N)=N QYPPJABKJHAVHS-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- 102100040243 Microtubule-associated protein tau Human genes 0.000 description 4
- 238000012347 Morris Water Maze Methods 0.000 description 4
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 4
- QYPPJABKJHAVHS-UHFFFAOYSA-P agmatinium(2+) Chemical compound NC(=[NH2+])NCCCC[NH3+] QYPPJABKJHAVHS-UHFFFAOYSA-P 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000003110 anti-inflammatory effect Effects 0.000 description 4
- 230000003920 cognitive function Effects 0.000 description 4
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical group O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229960004640 memantine Drugs 0.000 description 4
- 230000015654 memory Effects 0.000 description 4
- 230000006984 memory degeneration Effects 0.000 description 4
- 208000023060 memory loss Diseases 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 230000000770 proinflammatory effect Effects 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 3
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 3
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- 102000005701 Calcium-Binding Proteins Human genes 0.000 description 3
- 108010045403 Calcium-Binding Proteins Proteins 0.000 description 3
- 101000725401 Homo sapiens Cytochrome c oxidase subunit 2 Proteins 0.000 description 3
- 101000605127 Homo sapiens Prostaglandin G/H synthase 2 Proteins 0.000 description 3
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 3
- 102000004889 Interleukin-6 Human genes 0.000 description 3
- 108090001005 Interleukin-6 Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 3
- 230000008499 blood brain barrier function Effects 0.000 description 3
- 210000001218 blood-brain barrier Anatomy 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 208000025688 early-onset autosomal dominant Alzheimer disease Diseases 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 208000015756 familial Alzheimer disease Diseases 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 230000004112 neuroprotection Effects 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 108010026424 tau Proteins Proteins 0.000 description 3
- RATZLMXRALDSJW-UHFFFAOYSA-N 2-(2-ethyl-3H-benzofuran-2-yl)-4,5-dihydro-1H-imidazole Chemical compound C1C2=CC=CC=C2OC1(CC)C1=NCCN1 RATZLMXRALDSJW-UHFFFAOYSA-N 0.000 description 2
- KZMAWJRXKGLWGS-UHFFFAOYSA-N 2-chloro-n-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-n-(3-methoxypropyl)acetamide Chemical compound S1C(N(C(=O)CCl)CCCOC)=NC(C=2C=CC(OC)=CC=2)=C1 KZMAWJRXKGLWGS-UHFFFAOYSA-N 0.000 description 2
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- 239000012103 Alexa Fluor 488 Substances 0.000 description 2
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 2
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 2
- 206010003571 Astrocytoma Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102100023995 Beta-nerve growth factor Human genes 0.000 description 2
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 101000617536 Homo sapiens Presenilin-1 Proteins 0.000 description 2
- 108010044467 Isoenzymes Proteins 0.000 description 2
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 2
- 108010025020 Nerve Growth Factor Proteins 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- 108010039918 Polylysine Proteins 0.000 description 2
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 210000001642 activated microglia Anatomy 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 102000030484 alpha-2 Adrenergic Receptor Human genes 0.000 description 2
- 108020004101 alpha-2 Adrenergic Receptor Proteins 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000003542 behavioural effect Effects 0.000 description 2
- 210000005056 cell body Anatomy 0.000 description 2
- 229960002896 clonidine Drugs 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 150000001982 diacylglycerols Chemical class 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229950001765 efaroxan Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960003980 galantamine Drugs 0.000 description 2
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 2
- 210000000609 ganglia Anatomy 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000000971 hippocampal effect Effects 0.000 description 2
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 2
- 150000002462 imidazolines Chemical class 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 230000007334 memory performance Effects 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 210000004498 neuroglial cell Anatomy 0.000 description 2
- 231100000189 neurotoxic Toxicity 0.000 description 2
- 230000002887 neurotoxic effect Effects 0.000 description 2
- 230000007135 neurotoxicity Effects 0.000 description 2
- 239000002858 neurotransmitter agent Substances 0.000 description 2
- 230000001473 noxious effect Effects 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 229920000656 polylysine Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 208000037821 progressive disease Diseases 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000006886 spatial memory Effects 0.000 description 2
- 238000012453 sprague-dawley rat model Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- -1 4% paraformaldehyde Chemical compound 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 101150053137 AIF1 gene Proteins 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 102000007590 Calpain Human genes 0.000 description 1
- 108010032088 Calpain Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 102000004266 Collagen Type IV Human genes 0.000 description 1
- 108010042086 Collagen Type IV Proteins 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 102000010970 Connexin Human genes 0.000 description 1
- 108050001175 Connexin Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 101100396994 Drosophila melanogaster Inos gene Proteins 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 102100026693 FAS-associated death domain protein Human genes 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 102100039289 Glial fibrillary acidic protein Human genes 0.000 description 1
- 101710193519 Glial fibrillary acidic protein Proteins 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101000823051 Homo sapiens Amyloid-beta precursor protein Proteins 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000911074 Homo sapiens FAS-associated death domain protein Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 238000009015 Human TaqMan MicroRNA Assay kit Methods 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000013691 Interleukin-17 Human genes 0.000 description 1
- 108050003558 Interleukin-17 Proteins 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 102000010638 Kinesin Human genes 0.000 description 1
- 108010063296 Kinesin Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 208000009829 Lewy Body Disease Diseases 0.000 description 1
- 101150018665 MAPK3 gene Proteins 0.000 description 1
- 102000001776 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 101710115937 Microtubule-associated protein tau Proteins 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- 208000009668 Neurobehavioral Manifestations Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 description 1
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102100022033 Presenilin-1 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 238000010240 RT-PCR analysis Methods 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- VLSMHEGGTFMBBZ-UHFFFAOYSA-N alpha-Kainic acid Natural products CC(=C)C1CNC(C(O)=O)C1CC(O)=O VLSMHEGGTFMBBZ-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000006933 amyloid-beta aggregation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001760 anti-analgesic effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229940039856 aricept Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000029560 autism spectrum disease Diseases 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- 229960005539 bryostatin 1 Drugs 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000036978 cell physiology Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 210000004720 cerebrum Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000003931 cognitive performance Effects 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000007596 consolidation process Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 230000006862 enzymatic digestion Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 231100000318 excitotoxic Toxicity 0.000 description 1
- 230000003492 excitotoxic effect Effects 0.000 description 1
- 229940108366 exelon Drugs 0.000 description 1
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000020937 fasting conditions Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000007277 glial cell activation Effects 0.000 description 1
- 210000005046 glial fibrillary acidic protein Anatomy 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000010842 high-capacity cDNA reverse transcription kit Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 102000055060 human PSEN1 Human genes 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 description 1
- 229950006874 kainic acid Drugs 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000007787 long-term memory Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000037023 motor activity Effects 0.000 description 1
- 230000004973 motor coordination Effects 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 229940033872 namenda Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229940053128 nerve growth factor Drugs 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 230000009223 neuronal apoptosis Effects 0.000 description 1
- 230000006576 neuronal survival Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000001129 nonadrenergic effect Effects 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000003349 osteoarthritic effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000011302 passive avoidance test Methods 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical group C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 1
- 239000002644 phorbol ester Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 210000002243 primary neuron Anatomy 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000001003 psychopharmacologic effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 229940051845 razadyne Drugs 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000029865 regulation of blood pressure Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 210000003594 spinal ganglia Anatomy 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000012301 transgenic model Methods 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 230000003936 working memory Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Psychology (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及用于治疗神经退行性疾病的式2‑苯基‑6‑(1H‑咪唑‑1‑基)喹唑啉化合物或其药学上可接受的盐。神经退行性疾病是选自由阿尔茨海默病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病、朊病毒疾病、HIV‑相关痴呆和与神经退行性相关的任何形式的认知障碍组成的组中的疾病,优选阿尔茨海默病。
Description
技术领域
本发明提供2-苯基-6-(1H-咪唑-1-基)喹唑啉以治疗神经退行性疾病,优选阿尔茨海默病。
背景技术
神经退行性疾病(ND)是全世界死亡率和发病率不断上升的原因,尤其是在老年人中。它们包含高度扩散的病理,例如阿尔茨海默病、帕金森病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病和朊病毒病,并且特别关注这些综合征之间的相似性和差异性。
神经退行性疾病由于其普遍性、复杂的生物化学和病理学特征,对基础科学和临床医学提出了巨大的挑战。
因此相关治疗的新的机制代表了未满足的医学需求。
阿尔茨海默病(AD)是与进行性认知下降和记忆丧失有关的最常见的痴呆类型。它是美国第六大死亡原因,到2050年,估计将影响美国1400万人。
目前对AD的治疗几乎没有对症的益处,美国食品和药品监督管理局最近的批准是在2003年。自那以后,登记了超过400多项治疗AD的临床试验,在已报告结果的那些试验中,失败率接近100%。AD的治疗和预防(主要靶向累积在AD患者大脑中的β-淀粉样蛋白或成对螺旋丝tau蛋白)缺乏进展是令人沮丧的,因此需要改变视角,寻找新的途径和靶点,以获得新的有效的疾病调节剂。
AD的典型特征在于与细胞外淀粉样蛋白-β(Aβ)肽的累积相关的明显组织变化,这些肽来源于淀粉样蛋白前体蛋白(APP)的裂解和细胞内高磷酸化tau的沉积。Aβ和tau聚集体具有神经毒性,并触发大脑中的神经退行性过程,这表明Aβ和tau是驱动AD发病机制的核心。此外,许多影响AD风险的基因在小胶质细胞中表达(Zhang B,Cell,2013),在衰老和疾病期间,小胶质细胞和星形胶质细胞改变其激活表型。这些发现增加了先天免疫激活可能积极促成AD发病机制的可能性。当存在有害刺激(包括错误折叠的蛋白质例如Aβ)时,小胶质细胞在大脑中产生急性免疫反应。如果反应没有解决,小胶质细胞的慢性激活和星形胶质细胞的募集会转移它们的生理和有益功能。
咪唑(啉)/胍化合物通过与非肾上腺素受***点,即所谓的咪唑啉受体(EscribáP,Ann.N.Y.Acad.Sci.,1999)相互作用,引起中枢和外周效应。咪唑啉受体已被分为两种主要类型:Ⅰ1结合位点(BS)亚型,由药物如可乐定(clonidine)鉴定并参与血压调节;Ⅰ1结合位点,首先由咪唑克生(idazoxan)(混合I2BS和α2-肾上腺素能受体配体)鉴定,并以缺乏Ⅰ1-IBS和α2-肾上腺素能受体亲和力(例如2-BFI、BU224)的选择性配体为特征。此外,I3BS被鉴定为典型的咪唑啉亚型,存在于胰腺β细胞中,参与胰岛素分泌,并被依法克生(efaroxan)识别。
咪唑啉受体的其中一种内源性配体是胍丁胺,这是多胺生物合成中的胺中间体。胍丁胺广泛分布于体内并可能在大脑中充当神经递质和/或神经传递调节剂。除咪唑啉受体外,胍丁胺还与其他靶受体(例如α2-肾上腺素能、N-甲基-D-天冬氨酸(NMDA)以及血清素受体)以低亲和力结合,产生身体机能。
I2BS分布广泛,其在大脑中表达在神经元上,但主要在大部分位于线粒体外膜的神经胶质细胞上(Ruggiero DA,Brain Res.,1998)。
咪唑啉类药物的神经保护和抗炎作用已有报道(Regunathan S,Ann.N.Y.Acad.Sci.,1999),但I2BS药理学仍难以捉摸。I2受体代表一组存在于各种蛋白质上的结合位点,其性质和生物学意义尚不清楚(EscribáP,Ann.N.Y.Acad.Sci.1999)。
在过去30年中收集的一些实验证据表明,I2配体可能以不同的机制和在不同的神经变性模型中发挥至少部分神经保护作用。
长期以来,咪唑啉类药物的慢性治疗早已被证实可以增加星形胶质细胞的GFAP表达(Olmos G,Br.J.Pharmacol.,1994)。
在星形胶质细胞和巨噬细胞中,咪唑克生能够抑制诱导性NOS(iNOS)活性,从而降低NO-介导的神经毒性水平(Feinstein D,Mol.Pharmacol.,1999)。
BU224(选择性I2配体)已被证明可下调大鼠大脑皮层中的促凋亡因子,因此,可以通过抑制大脑中典型凋亡信号的关键成分来介导神经保护作用(Garau C J,Psychopharmacol.,2013)。
2-BFI(选择性I2配体)在缺血性中风的体外和体内模型中都显示出神经保护作用。体外2-BFI预防缺氧缺糖星形胶质细胞脂质过氧化和线粒体凋亡(Tian J,J.Neurosci.Res.,2018),而在由大脑中动脉闭塞引起的脑损伤中,短暂脑缺血的大鼠模型中,2-BFI诱导Bcl-2表达(在脑缺血时,在神经元存活中起关键作用的基因)(Han Z,BrainRes,2010)并保护血脑屏障完整性,降低基质金属蛋白酶9(MMP-9)的表达并上调紧密连接蛋白和Ⅳ型胶原(Zhang ZJ,Stroke Cerebrovasc.Dis.,2018)。
I2受体配体以低亲和力结合NMDA受体,并以非竞争性和可逆的方式调节其活性,类似于美金刚胺(memantine)在体外和体内降低NMDA-介导的谷氨酸毒性(Jiang SX,Eur.J.Pharmacol.,2010)。I2咪唑啉类药物通过降低Erk1/2激活来抑制Aβ-诱导的神经元毒性(Montolio M,J.Med.Chem.,2012)。
用2-BFI的慢性治疗减轻实验性自身免疫性脑脊髓炎(多发性硬化的小鼠模型),恢复B-CK和CaATPase酶活性,并在基础水平维持钙依赖性钙蛋白酶激活(Wang P,Biochem.Biophys.Res.Commun.,2011),降低促炎细胞因子IL-17A和IFN-γ的水平,和增加抗炎细胞因子IL-10的水平(Zhu YB,Neurochem.Res.,2015)。
在AD模型中(通过在大鼠海马中注射Aβ1-42),2-BFI改善学习和记忆能力,降低氧化应激,下调炎症因子的释放和抑制神经细胞凋亡(Tian JS,J.Integr.Neurosci.,2017)。
BU224对红藻氨酸诱导的兴奋性毒性信号具有部分神经保护作用(Keller BJ,Psychopharmacol.,2016)。
使用BU224的急性治疗增加了海马p-FADD/FADD比率(细胞存活指数)并减少了p35裂解为神经毒性的p25(Abás S.ACS Chem.Neurosci.,2017)。
内源性咪唑啉受体配体胍丁胺的治疗显著改善了糖尿病大鼠的认知功能,恢复了诱导的记忆缺陷(Bhutada P,Prog.Neuro-Psychopharmacology Biol.Psychiatry 2012)。
另一方面,在衰老和AD患者的大脑中,使用放射性配体结合试验观察到I2R密度增加,这可能是由于它们位于星形胶质细胞中(García-Sevilla,Neurosci.Lett.,1998)。
蛋白激酶C(PKC)是丝氨酸/苏氨酸蛋白激酶的磷脂依赖性家族,在大脑中构成广泛的信号网络。分子克隆研究揭示了12种PKC同工酶,可分为三个亚组:(1)经典PKC,(2)新型PKC,和(3)非经典PKC。PKC亚型在包括学习和记忆在内的各种认知功能中起着关键作用。特别地,被归类为新型PKC(其激活不需要钙)的PKCε是佛波酯/二酰基甘油(DAG)敏感的且与钙无关的丝氨酸/苏氨酸激酶。它是各种信号传导事件的关键调节器,因此它在几个亚细胞位置存在的需求通过同工酶特异性驱动蛋白的激酶易位(translocation)来满足。激酶的异常易位可能会误导信号输出,从而对细胞生理学造成损害。由于这种复杂的生物学特性,其在神经退行性疾病中的作用仍有争议。虽然一些论文表明抑制PKCε激活导致对神经退行性疾病的整体保护(例如:in Alzhemeir's disease Zara S.Brain Research 2011;in ischemia induced neurodegeneration,Kumar V,J Neuro Res.2019),过去的大多数论文都指出了PKCε激活在这些疾病中的保护作用。这个概念导致了该激酶的激活剂(苔藓抑素-1)被提议作为阿尔茨海默病的临床候选物,例如在US 2008/0004332和US2016/0025704中。在前者中,其表明,外周组织中的PKC抑制剂可能与PKC激活剂有关,只是为了抑制外周组织中激活PKC可能引起的副作用,其中“外周组织是指脑以外的组织”。遗憾的是,2017年5月,有消息称,在概念研究的Ⅱ阶段证据中,这种使用PKCε苔藓抑素-1的方法未能达到主要终点,该终点衡量了严重障碍量表(SIB)评分相对于安慰剂的改善。
发明内容
发明人发现,式2-苯基-6-(1H-咪唑-1-基)喹唑啉化合物(也称为CR4056)可用于治疗神经退行性疾病,优选阿尔茨海默病。
这种分子结合了1)对I2结合位点的强活性,2)对PKCε向神经元中的细胞膜易位的持久抑制,以及3)跨越血脑屏障的惊人能力。在记忆障碍和阿尔茨海默病模型中,这三个特征的结合使CR4056产生了令人惊讶的效果。这导致了特别的创新,因为现有技术明确排除了在神经退行性疾病的治疗中使用脑渗透PKC抑制剂。
因此,在第一方面,本发明涉及用于治疗神经退行性疾病的式2-苯基-6-(1H-咪唑-1-基)喹唑啉化合物或其药学上可接受的盐,其中神经退行性疾病是选自由阿尔茨海默病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病、朊病毒疾病、HIV-相关痴呆组成的组中的疾病。
当在本发明中提到神经退行性疾病时,其是指选自由慢性、进行性紊乱组成的组中的疾病,其特征在于中枢神经***(CNS)的离散区域中神经元的逐渐丧失。
根据本发明的神经退行性疾病是选自由由阿尔茨海默病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病、朊病毒疾病和HIV-相关痴呆组成的组中的疾病,优选阿尔茨海默病。
这种神经退行性疾病发展的潜在机制尚不清楚,但及时和良好控制的炎症反应对于CNS的完整性和正常功能至关重要。
化合物2-苯基-6-(1H-咪唑-1-基)喹唑啉(也称为CR4056)是第一类咪唑啉-2受体配体,其特征在于在炎症、神经源性、神经病性、术后、纤维肌痛样和骨关节炎疼痛的不同动物模型中具有有效的镇痛活性(WO2008014822 A1、WO2009152868 A1、Ferrari F,JPainRes,2011;Lanza M,B.J.of Pharmacol.,2014)。
此外,CR4056被赋予持久(但仍然可逆)的能力来抑制炎症刺激引发的PKCε向初级神经元的细胞膜的易位。这种持久的活性是CR4056的特征,而其他抗炎或镇痛化合物不具有这种活性。然而,这种活性是咪唑克生(典型的I2受体拮抗剂)抗性,因此似乎独立于由I2配体诱导的经典路径。不受任何理论的束缚,发明人认为抑制由炎症刺激引发的PKCε向神经元中的质膜的易位可能是控制神经退行性的令人惊讶的更好的靶点,并且发现CR4056是做此事的最佳候选物。
最后,CR4056被赋予了穿过血脑屏障和靶向中枢神经***的特殊能力:以30mg/kg的剂量悬浮在0.5%甲基纤维素(Methocel)中,单次口服给药1h后,研究了大鼠大脑中CR4056的存在。大脑中CR4056的平均水平为32272ng/g。平均脑/血浆比率为11.8,表明CR4056在大脑中具有显著的集中能力。
发明人在体外和体内模型(转基因或药理学)中测试了CR4056用于神经退行性疾病,尤其是阿尔茨海默病,并令人惊讶地发现,CR4056显著降低了小胶质细胞的激活,从而有助于神经保护,其显著改善了认知表现,并能够逆转阿尔茨海默病转基因和药理学模型中的记忆障碍。
从安全性的角度来看,即使在超药理学(suprapharmacological)浓度下,并且考虑到CR4056对大脑的特殊趋向性,CR4056在大鼠中也没有表现出中枢不良作用。特别地,既没有观察到神经行为的变化(通过欧文(Irwin)测试评估),也没有观察到运动协调和运动活动的障碍(通过旋转法和野外试验评估)。这些发现表明CR4056可能是用于治疗神经退行性疾病,尤其是阿尔茨海默病的安全药物。
附图说明
图1报告了CR4056对缓激肽(BK 1μM)诱导的PKCε易位的效果的时程(A)和洗脱(B)。在A组中,空心符号代表在没有药物的情况下,BK刺激后,对PKCε易位阳性的神经元的百分比。填充符号表示在用BK+CR4056刺激30秒之前,用CR4056(10μM)预孵育不同时间的神经元。第一个填充符号表示CR4056与BK共孵育30秒的效果,第二个填充符号表示CR4056预孵育10秒,最后一个表示CR4056预孵育24小时。CR4056的作用在任何时候都非常显著(t检验,p<0.05,n=6)。在B组中,在预孵育CR4056(10μM)之前(空心符号)和在预孵育CR4056之后在不同的时间间隔(从10分钟到8小时)(填充符号)评估了BK诱导的PKCε易位。第一个数据点是在10分钟预孵育结束时获得的,此时CR4056仍然存在。在大量冲洗后获得后续数据点,以确保从细胞外溶液中完全去除药物(n=3)。
图2报告了注射CFA后,72小时时脊髓小胶质细胞激活的结果。同侧L5 SC背角小胶质细胞激活的定量确定为Iba1-阳性小胶质细胞的数量,在所分析的选定浅层框架内显示出明显肿胀的细胞体和减少的过程。数据代表5只动物/组的平均值。普通单因素ANOVA,然后是邓尼特(Dunnet’s)多重比较(**p<0.05)。
图3报告了东莨菪碱诱导的记忆丧失模型中被动回避试验的结果。用东莨菪碱(Sco,1mg/kg)或生理溶液(Sal)治疗的大鼠接受CR4056 10mg/kg一天两次(bid)或其载体(MC)。t Student测试。*p<0.05;**p<0.01(n=6)。
图4报告了在东莨菪碱诱导的记忆丧失模型中的Morris水迷宫(Morris WaterMaze)试验的结果。用东莨菪碱(Sco,1mg/kg)或生理溶液(Sal)治疗的大鼠接受CR405620mg/kg/die或其载体(MC)。数据代表了四天内到达隐藏平台的所花费的平均时间。双向ANOVA。图基(Tukey)对比试验。**p<0.01。
图5报告了在东莨菪碱诱导的记忆丧失模型中的新物体识别试验(Novel Objectrecognition test)的结果。数据表示为在测试阶段探索新老物体所花费时间的百分比。*p<0.05;**p<0.01;t Student测试(n=6)。
图6报告了在阿尔茨海默病转基因5XFAD小鼠模型中的新物体识别试验的结果。(Obj C=新物体)*p<0.0001,不成对t Student测试。
具体实施方式
发明人发现化合物2-苯基-6-(1H-咪唑-1-基)喹唑啉(也称为CR4056)可用于治疗神经退行性疾病,优选阿尔茨海默病。
因此,在第一方面,本发明涉及用于治疗神经退行性疾病的式2-苯基-6-(1H-咪唑-1-基)喹唑啉化合物或其药学上可接受的盐,其中神经退行性疾病是选自由阿尔茨海默病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病、朊病毒疾病和HIV-相关痴呆组成的组中的疾病。
当在本发明中提及神经退行性疾病时,其是指选自由慢性、进行性紊乱组成的组中的疾病,其特征在于中枢神经***(CNS)的离散区域中神经元的逐渐丧失。
神经退行性疾病是选自由阿尔茨海默病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病、朊病毒疾病和HIV-相关痴呆组成的组中的疾病,优选阿尔茨海默病。
这种神经退行性疾病发展的潜在机制尚不清楚,但及时和良好控制的炎症反应对于CNS的完整性和正常功能至关重要。
本发明还提供了用于治疗或预防有此需要的受试者发生神经退行性疾病的方法,所述方法包括向受试者施用治疗有效量的根据本发明的化合物或药物组合物,从而治疗或降低发生神经退行性疾病的风险。
根据本发明,所述神经退行性疾病是选自由阿尔茨海默病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病、朊病毒疾病和HIV-相关痴呆组成的组中的疾病,优选阿尔茨海默病。
化合物2-苯基-6-(1H-咪唑-1-基)喹唑啉可以以游离碱或以盐的形式使用。优选地,药学上可接受的盐是选自盐酸盐、氢溴酸盐、硫酸氢盐和硫酸盐、马来酸盐、富马酸盐、草酸盐、甲磺酸盐、琥珀酸盐、抗坏血酸盐、酒石酸盐、醋酸盐、水杨酸盐、柠檬酸盐、天冬氨酸盐、乙二胺四乙酸盐、苯甲酸盐和谷氨酸盐的盐。药学上可接受的盐的其他例子在S.M.Berge et al,J.Pharm.Sci.1977,66,2中有报道。
化合物2-苯基-6-(1H-咪唑-1-基)喹唑啉也可以是多晶型形式或水合物形式,如EP2438058A中所述。
在第二方面,本发明涉及用于治疗神经退行性疾病的药物组合物,其包含化合物2-苯基-6-(1H-咪唑-1-基)喹唑啉或其药学上可接受的盐和载体,其中神经退行性疾病是选自由阿尔茨海默病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病、朊病毒疾病和HIV-相关痴呆组成的组中的疾病。
优选地,本发明的组合物用于治疗阿尔茨海默病。
所用的组合物还可以包含药学上可接受的辅料,并且可以以适合所需施用途径的药物形式施用。
药学上可接受的添加剂可以是辅料、配体、分散剂、着色剂、保湿剂,通常用于制备口服施用的片剂、胶囊、丸剂、溶液、悬浮液、乳剂。也可以考虑用于肠胃外施用的可注射溶液,包括皮下、脊髓和经皮施用。
根据本发明的药物组合物优选用于静脉内、口服、经皮、鞘内、鼻内、腹膜内或肌肉内施用。
根据本发明的药物组合物可以单独使用,或者与一种或多种其他的药物组合使用,或者可以包含一种或多种其他的药物。这些药物可以是已知用于治疗神经退行性疾病(优选阿尔茨海默病)的药物。
用于治疗神经退行性疾病的组合物可以包含2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)或药学上可接受的盐,相对于单一剂型,其用量为15至250mg,导致每日摄入量为15至500mg。
本发明还涉及同时、依次或分别用于治疗神经退行性疾病的组合制剂,其包含CR4056或其药学上可接受的盐和NMDA(N-甲基-D-天冬氨酸)受体拮抗剂和/或乙酰胆碱酯酶抑制剂中的至少一种,其中神经退行性疾病是选自由阿尔茨海默病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病、朊病毒疾病和HIV-相关痴呆组成的组中的疾病,优选阿尔茨海默病。
CR4056以上述剂量施用,可选地与属于目前被批准用于治疗阿尔茨海默病认知症状的药物类别的药物(即,NMDA(N-甲基-D-天冬氨酸)受体拮抗剂和乙酰胆碱酯酶抑制剂)组合施用。
特别地,NMDA受体拮抗剂为美金刚胺,乙酰胆碱酯酶抑制剂选自多奈哌齐、卡巴拉汀和加兰他敏。
美金刚胺(或)、多奈哌齐卡巴拉汀和加兰他敏(或)的剂量应符合制造商的建议,分别是Namenda标签信息(2007)、Aricept标签信息、Exelon标签信息(2006)和Razadyne标签信息(2008)。
现在将通过使用神经退行性疾病的体外和体内模型(转基因和非转基因)参考实施例来描述本发明。
实验部分
实施例1:2-苯基-6-(1H-咪唑-1-基)喹唑啉对炎症性基因表达的体外影响
方法
这些实验使用星形胶质细胞、人成胶质细胞瘤星形细胞瘤细胞系U373 MG(乌普萨拉)模型。在增补有10%FBS的DMEM培养基中,在37℃和CO2下,培养贴壁细胞。在铺板后72小时,用根据EP2066653制备的2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)(10μM)治疗细胞1h,然后再用促炎细胞因子IL-1β(2ng/mL)刺激6和24h。
在潜伏期结束时,获得总RNA,并使用高容量cDNA逆转录试剂盒(赛默飞世尔科技公司)进行逆转录。COX-2、IL-1β、IL-6和TNFα的表达水平通过RT-PCR分析进行评估,使用应用生物***7500快速实时PCR***(Applied Biosystems 7500Fast Real-Time PCRSystem),使用特定的TaqMan分析,作为内源性对照,使用18S预开发的分析(赛默飞世尔科技公司)。根据赛默飞世尔科技公司对基因表达相对定量的具体说明,对18S扩增值进行的标准化的数据分析。所有单个数据都是每个样本至少三次不同测量的结果。
结果
在孵育6小时后,2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)降低了COX2和IL-1β基因表达,在基因表达方面,对COX2的抑制作用为45%,对IL-1β的抑制作用为20%。此时,IL-6和TNFα的基因表达似乎尚未受到CR4056的调节。
刺激24小时后,CR4056降低了所分析的所有炎症标记物的基因表达,在基因表达方面,对COX2的抑制作用为48%,对IL-1β的抑制作用为29%,对IL-6的抑制作用为39%,对TNFα的抑制作用为52%,如下表所示。
表I
在用IL-1β2ng/ml刺激并暴露于10μM CR4056中指定时间的U373细胞中观察到的基因表达抑制百分比。
结论
上述报道的结果表明,CR4056对星形细胞瘤细胞系中促炎细胞因子的产生具有调节作用。这种作用可能有助于神经保护作用。
实施例2:2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)对PKCε向培养神经元中的质膜易位的体外作用
方法
小心地去除神经干和***后,从新分离的棘突获得大鼠背根神经节(DRG)。将较大的神经节切成2-4个小块,然后在37℃下,在溶于杜尔贝科改良Eagle’s培养基(DMEM)中的0.125%胶原酶(Worthington,Freehold,NJ)中孵育1小时,该培养基含10%胎牛血清(FBS)加1%青霉素/链霉素和1%L-谷氨酰胺(Euroclone,米兰,意大利)。酶消化后,机械分离神经节,在含有带玻璃底盖玻片的孔的培养皿中(预先涂有10μg/mL聚赖氨酸(poly-L-lysine)和20μg/ml层粘连蛋白,西格玛奥德里奇,米兰,意大利),以一定的密度铺板神经元,使得神经元以单层覆盖盖玻片表面约30%。如上所述,细胞在DMEM孵育2-3天,添加1.5μg/ml胞嘧啶1-d-***呋喃糖苷(ARA-C,西格玛奥德里奇)以减缓非神经元细胞的增殖,并添加100μg/ml神经生长因子(NGF,西格玛奥德里奇)以增加细胞健康和刺激时与PKCε易位相关的受体的表达。与磷脂酶C路径偶联的膜受体的激活导致PKCε从细胞质向质膜易位。为了研究PKCε行为,采用了成熟的技术(Vellani V,Neuroscience,2006)。这项技术涉及激活由炎性介质如缓激肽(BK)或前激动素(prokineticin)2(PK2)快速诱导的PKCε(30秒),随后用在磷酸盐缓冲盐水(PBS,50%稀释)中的4%多聚甲醛和4%蔗糖固定,对PKCε进行染色,并量化观察到易位的神经元数量。将CR4056预先施加在培养基中10min或与刺激物共同施用。固定后,用0.2%Triton X-100(西格玛奥德里奇,米兰,意大利)透化细胞,并暴露于对PKCε高度特异的兔多克隆抗体中过夜。在大量冲洗后,用二抗(1:200稀释度Alexa Fluor488山羊抗兔,赛默飞世尔科技公司,蒙扎,意大利)在室温下在黑暗中施用2-4小时来显现PKCε,用共聚焦显微镜(徕卡SP2,徕卡,瑞士)通过测量沿着穿过细胞质和细胞膜的线的荧光强度来检测显示PKCε易位的细胞,从而避开细胞核。整个细胞的质膜荧光强度是平均细胞质强度的1.5倍或更高的神经元被认为是阳性的。
结果
CR4056剂量依赖性地抑制用BK或PK2获得的PKCε易位,IC50值分别为0.20和0.17μM。当施用CR4056 10分钟时,剂量-反应曲线在约10μM处接近饱和。在不同的时间间隔测试该浓度,以研究CR4056作用的动力学。延长(不超过24小时)或减少(10秒)预孵育的时间,并没有改变作用的程度。然后分析了洗脱该药物作用所需的时间。在图1A和B中,报道了施用CR4056(10μM)后不同时间点的PKCε易位:首先,在施用10分钟后,然后,在用大量体积的培养基(DMEM+10%FBS,37℃)反复、持久洗涤后,预期从细胞外环境去除任何微量的CR4056(洗脱)。洗脱后,CR4056的作用最多保持1小时不变,然后缓慢下降,并在3-4小时内完全逆转。
然后测试PKCε易位试验对咪唑克生的敏感性。在高浓度(10和100μM)下,向1μMCR4056预施用咪唑克生10分钟,该浓度诱导PKCε易位的亚最大阻断。两种浓度的咪唑克生都完全无效。
结论
上述报道的结果表明,CR4056有效地阻断了受促炎刺激攻击的神经元中的PKCε易位,CR4056作用起效快,但从细胞中去除非常慢,并且CR4056用于实现这种作用的路径是咪唑克生抗性的,证明了非经典I2受体的参与。除了其已确定的I2-驱动作用,CR4056在神经元中抗炎活性的这种特殊机制,可能有助于该产品在神经退行性过程和认知障碍中的整体疗效。
实施例3:2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)对CFA炎症模型中的小胶质细胞活化的体内作用
方法
通过免疫荧光染色评估小胶质细胞激活,在完全弗氏佐剂(CFA)模型中,测量同侧L5脊髓中的离子钙结合接头分子1(Iba-1)的表达。
通过向大鼠右后爪的趾面注射100μL CFA(1mg/mL,用盐水以1:1稀释)诱导单侧炎症。
在CFA后72小时,施用CR4056(6mg/kg,os),90分钟后,用过量的氨基甲酸乙酯(1.5g·kg-1,i.p.)深度麻醉动物,然后经心灌注250mL 0.9%含1%肝素的盐水(5000UI·mL-1),随后是500mL 10%***(即4%多聚甲醛,Bio-Optica Spa,米兰,意大利)。采集脊髓L5段,在4℃固定后过夜,并嵌入石蜡块中用于切片。脊髓的横切面用全自动旋转切片机以5μm的厚度切片,安装在涂有聚-赖氨酸的载玻片上,然后进行免疫荧光处理。使用10mM柠檬酸盐缓冲液(pH 6.0)在90℃下回收抗原20分钟。在室温下,切片用在含有0.3%triton-X的PBS中的10%正常马血清封闭90分钟,然后在4℃下与兔抗离子化钙结合配体(rabbit anti-ionized calcium-binding adapter)分子1(Iba1)初级多克隆抗体(1:350;Wako Chemicals,诺伊斯,德国#019-9741)一起孵育过夜。为了二次检测,在室温下,将切片与Alexa-Fluor 488驴抗兔二次抗体(1:400;赛默飞世尔科技有限公司,沃尔瑟姆,MA,美国#A-21206)孵育1小时。载玻片用含4’,6-二脒基-2-苯基吲哚或DAPI(西格玛奥德里奇,米兰,意大利#F6057)的FluoroShield固定介质固定,以复染细胞核。脊髓切片用InvitrogenEVOS FL自动细胞成像***(赛默飞世尔科技有限公司,沃尔瑟姆,MA,美国)进行可视化。每个切片的对侧在腹角有小切口。以Paxinos和Watson(Paxinos和Watson,1982)的大鼠脑图谱为参考,确定了背角的Ⅰ-Ⅲ层。对于每个切片,使用所有切片上一致的暴露时间,在20倍放大下捕获L5脊髓的同侧和对侧背角(Ⅰ-Ⅲ层)的代表性图像,然后分析。手动计数显示变形/激活状态(即明显肿胀的细胞体和减少的过程)的Iba-1阳性小胶质细胞。结果表示为显示激活状态的Iba1-阳性小胶质细胞数量的同侧/对侧比率的百分比。对每只动物(每组n=5)的6个非连续切片进行分析,并对结果取平均。
结果
CFA-诱导的关节炎大鼠模型是慢性炎性疼痛的范例。在外周组织损伤中,移植物内注射CFA导致对有害热的敏感性增加以及对机械触觉刺激的敏感性增加,并诱导L5脊髓同侧与对侧背角的Ⅰ-Ⅲ层中Iba1-阳性、形态激活的小胶质细胞(即小胶质细胞激活)比率显著增加。
在单次施用(6mg/kg,os)后,CR4056完全恢复了之前通过CFA治疗激活的小胶质细胞的基础状态(图2)。
结论
在几种疾病的过程中,小胶质细胞失去其稳态分子特征和功能,变成慢性炎症并引发有害影响。这对于包括阿尔茨海默病、肌萎缩性脊髓侧索硬化、多发性硬化、帕金森病的神经退行性疾病,衰老和自闭症谱系障碍(Butovsky O,Nature Rev Neuroscience2018,Henstridge CM,Frontiers in Cellular Neuroscience,2019;Wes PD,Glia 2016;Salter,MW,Nat.Med.,2017)以及慢性疼痛(Malcangio M,Pain,2016)是显然的。
在该动物模型中,CR4056显著降低了小胶质细胞的激活,这通过Iba1-阳性细胞的减少得到了加强,从而有助于神经保护。
实施例4:2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)对东莨菪碱诱导的记忆障碍模型的体内作用:被动回避
方法
东茛菪碱是一种非选择性毒蕈碱受体拮抗剂,可阻断毒蕈碱乙酰胆碱受体的活性,并伴随出现短暂性认知遗忘和电生理改变,类似于在阿尔茨海默病中观察到的情况。因此,施用东莨菪碱可被认为是阿尔茨海默病的精神药理学模型(Lenz RA,Psychopharmacology(Berl),2012)。
被动回避是记忆障碍的行为模式。
该仪器由两个隔间的隔室组成:由门隔开的亮室和暗室。将大鼠放在亮室的中央,两个室之间的门是关着的。4秒后,将门打开,记录等待时间,即大鼠将所有四只爪子进入暗室的所花费的时间。
一旦大鼠在暗室里完全移动,门就被关闭,并立即通过网格地板发出轻微的足震。因此,在最初阶段,动物了解到移动到暗室有负面的后果。
训练40个小时后,将大鼠放在亮室中,除了不对网格地板施加足震之外,遵循相同的训练程序。记忆表现与逃离亮室的潜伏期呈正相关。
为了诱导记忆障碍,在学习试验前30分钟施用东莨菪碱(1mg/kg sc)。
学习试验后,立即口服施用CR4056(10mg/kg bid(一天两次)),以避免因其镇痛作用而可能出现的偏差。
结果
图3显示,在测试日,与训练相比,假手术组动物(未用东莨菪碱治疗)显著增加了从亮室逃离的潜伏期。在用东莨菪碱治疗的动物中,潜伏期没有增加。
CR4056 10mg/kg一天两次(bid)可抵消东莨菪碱诱导的记忆障碍(表现为逃离潜伏期增加)。
用CR4056治疗的假手术组动物的逃离潜伏期与其载体(甲基纤维素,MC)没有区别。
结论
CR4056能够逆转阿尔茨海默病和痴呆症药理模型中的记忆障碍。
实施例5:2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)对东莨菪碱诱导的大鼠记忆障碍行为模型的影响:Morris水迷宫
方法
Morris水迷宫试验用于评估认知功能,分为两个阶段:首先是对隐藏平台的获取和空间定位,随后是对获取的信息进行处理、巩固、保留和检索,以成功定位逃离水的平台。
地点导航要求大鼠学会从任何起始位置游向逃离平台,从而获得对平台空间位置的长期记忆。将动物放入水池的不同象限,记录到达隐藏平台所需的时间和距离。将各种的物体放置在测试室里,这样动物们就可以利用这些视觉线索在迷宫中导航。在反复进入迷宫后,动物们在定位平台时变得越来越有效率,从而通过学习平台相对于远端视觉线索的位置来逃离水。
为了诱导记忆障碍,在试验前30分钟施用东莨菪碱(1mg/kg,sc),而在试验前60分钟施用CR4056(20mg/kg,os)。四天内进行了四次试验,报告的最终潜伏期是所有天数的平均值。
结果
CR4056 20mg/kg可逆转东莨菪碱所引发的记忆障碍。如图4所示,与对照组相比,用东莨菪碱治疗的大鼠需要更多的时间来定位隐藏平台。与仅用东莨菪碱治疗的动物相比,共同施用CR4056与东莨菪碱显著减少了到达平台所需的时间。
结论
用CR4056治疗逆转了东莨菪碱治疗获得的痴呆动物模型为特征的记忆能力的障碍。
实施例6:2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)在东莨菪碱诱导的记忆障碍小鼠模型中的作用:新物体识别
方法
基于小鼠识别竞技场测试中提出的各种物体的能力,新物体识别测试被用于评估认知功能。在训练阶段,将一对相同的物体放置在笼子里进行测试。第一阶段24小时后,在测试阶段,用新的不同的物体替换两个物体中的一个。在训练和测试阶段,记录每个物体的探索时间。小鼠的典型方法是在训练阶段对物体进行类似的探索,在测试阶段偏好新物体。施用会使认知能力恶化的物质(即东莨菪碱)导致旧物体的提示被删除,两个不同物体被同等探索。
在训练前20分钟,腹腔注射(ip)施用东莨菪碱1mg/kg,而在训练前40分钟,os施用CR4056 620mg/kg。
结果
CR4056 6和20mg/kg增加了测试阶段探索新物体(偏好)的时间。仅用东莨菪碱治疗的小鼠对新物体没有偏好(图5)。
结论
在东莨菪碱诱导的痴呆动物模型中,CR4056剂量依赖性地改善了小鼠的记忆能力,证实了以前在大鼠中获得的结果。
实施例7:2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)在阿尔茨海默病转基因5XFAD小鼠模型中的作用:新物体识别
方法
使用具有瑞典(K670N/M671L)、佛罗里达(I 716V)和伦敦(V717 I)家族性阿尔茨海默病(FAD)突变的过表达人淀粉样前体蛋白(APP695)的转基因5XFAD小鼠,以及具有M146L和L286V FAD突变的人早老素1(PS1)作为阿尔茨海默病模型。
将6月龄雌性转基因5XFAD小鼠和野生型对照(WT)口服(灌胃)30mg/kg的CR4056或载体,每天一次,持续10天(n=4WT/载体、8WT/CR4056、25XFAD/载体以及35XFAD/CR4056)。重复治疗后,使用新的物体识别任务测试海马依赖记忆。物体识别测试测量工作和空间记忆。在训练阶段,将动物放在竞技场上,用大的塑料砖建造物品。在测试阶段,一个物体被一个新物体替换。动物被送回竞技场,允许其探索。观察并记录了物体的探索。小鼠应该认识到新物体已经被放置,因此探索这个物体的时间更长。
结果
在测试日,5XFAD载体组显示出认知缺陷,而用CR4056治疗的5XFAD动物显示出工作和空间记忆的显著改善(图6)。
结论
5XFAD小鼠是阿尔茨海默病模型,其特征为神经内Aβ聚集、神经退行性、神经元丢失、伴有胶质细胞活化的记忆障碍(Oakley H,The journal of Neuroscience,2006;Mirzaei N.Glia2006)。
在该转基因模型中,CR4056显著改善记忆表现,与东莨菪碱诱导的痴呆药理学模型中获得的结果一致。
实施例8:2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)的脑渗透
方法
采用LC/MS/MS法测定大鼠血浆以及大鼠脑和血浆中的CR4056。来自哈兰(Harlan)的雄性斯普拉克·道利(Sprague Dawley)大鼠以30mg/kg的剂量口服CR4056悬浮液(0.5%甲基纤维素)。每组3只动物通过灌胃进行口服施用(5ml/kg)。治疗后1小时,在血浆和大脑中检测到该化合物。
将每只大鼠的大脑称重并切成两半。用两种不同的方法对每个大脑半球进行称重和均质化。一种是通过Ultra turrax试管驱动(IKA)进行液化,加入相对于大脑半球重量的三倍的等分缓冲溶液(10mM甲酸铵pH3.5)。然后将30μl的提取液加入到在1.5ml eppendorf管中的0.25ml甲醇中,在4℃下以13500rpm涡旋混合并离心5min。将上清液转移到96孔深的2mL圆板(Axygen)中,并注入到LC/MS/MS***中。第二种是用米克洛粉碎机(MikroDismembrator)(Sartorius)进行冷冻研磨。将每个大脑半球的称重,放入20mL带有钢珠的特氟隆容器中(7,85g/ml,dia 10mm),并的浸入液氮中冷冻5分钟。用米克洛粉碎机以2500rpm研磨深度冷冻的大脑30秒,重复冷冻/研磨循环两次。精确称重一部分粉末(大约10mg),放入1.5ml eppendorf管,然后加入0.25ml甲醇。在4℃下以13500rpm涡旋混合并离心5min后,将上清液置于96孔深的2mL圆板(Axygen)中,并注入LC/MS/MS***。用于均质化的两种方法得到了相似的结果,表明两种方法的提取效率相似。
结果
在禁食条件下(大鼠在口服(PO)施用后60分钟被杀死),雄性斯普拉克·道利大鼠口服施用CR4056悬浮液(30mg/kg)后,单独的血浆和大脑水平以及大脑血浆比率如下表所示。
大鼠 | 实际 | 途径 | 大鼠 | 实际 | 血浆 | 平均大脑 | 大脑 |
ID | 剂量 | 体重 | 时间 | 浓度 | 浓度 | /血浆 | |
(mg) | (kg) | (h) | (ng/mL) | (ng/g) | 比率 | ||
1 | 6.6 | PO | 0.216 | 1 | 2860 | 33580 | 11.7 |
2 | 6.6 | PO | 0.212 | 1 | 2860 | 33492 | 12.4 |
3 | 6.6 | PO | 0.212 | 1 | 2430 | 27745 | 11.4 |
平均值 | 6.6 | PO | 0.213 | 1 | 2717 | 32272 | 11.8 |
因此,该实验证明CR4056能够有效进入大脑,从而直接对中枢神经***(CNS)产生作用。
Claims (9)
1.用于治疗神经退行性疾病的式2-苯基-6-(1H-咪唑-1-基)喹唑啉化合物或其药学上可接受的盐,其中所述神经退行性疾病是选自由阿尔茨海默病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病、朊病毒疾病和HIV-相关痴呆组成的组中的疾病。
2.根据权利要求1所用的化合物,其中所述神经退行性疾病是阿尔茨海默病。
3.根据权利要求1或权利要求2所用的化合物,其中2-苯基-6-(1H-咪唑-1-基)喹唑啉的药学上可接受的盐是选自盐酸盐、氢溴酸盐、硫酸氢盐和硫酸盐、马来酸盐、富马酸盐、草酸盐、甲磺酸盐、琥珀酸盐、抗坏血酸盐、酒石酸盐、醋酸盐、水杨酸盐、柠檬酸盐、天冬氨酸盐、乙二胺四乙酸盐、苯甲酸盐和谷氨酸盐的盐。
4.用于治疗神经退行性疾病的药物组合物,其包含式2-苯基-6-(1H-咪唑-1-基)喹唑啉化合物或其药学上可接受的盐和载体,其中神经退行性疾病是选自由阿尔茨海默病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病、朊病毒疾病和HIV-相关痴呆组成的组中的疾病。
5.根据权利要求4所用的组合物,其中所述神经退行性疾病是阿尔茨海默病。
6.根据权利要求4或5所用的组合物,其中相对于单一剂型,2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)或药学上可接受的盐的含量为15至250mg,导致每日摄入量为15至500mg。
7.根据权利要求4-6中任一项所用的组合物,其中所述组合物包含至少一种其他药物。
8.一种同时、依次或分别用于治疗神经退行性疾病的组合药物制剂,其包含2-苯基-6-(1H-咪唑-1-基)喹唑啉(CR4056)或其药学上可接受的盐和NMDA(N-甲基-D-天冬氨酸)受体拮抗剂和/或乙酰胆碱酯酶抑制剂中的至少一种,其中所述神经退行性疾病是选自由阿尔茨海默病、路易体痴呆、额颞叶痴呆、肌萎缩性脊髓侧索硬化、亨廷顿病、朊病毒疾病和HIV-相关痴呆组成的组中的疾病。
9.根据权利要求8所用的组合药物制剂,其中所述神经退行性疾病是阿尔茨海默病。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP19173783.2A EP3735974A1 (en) | 2019-05-10 | 2019-05-10 | Use of 2-phenyl-6-(1h-imidazol-1-yl)quinazoline for treating neurodegenerative diseases, preferably alzheimer's disease |
EP19173783.2 | 2019-05-10 | ||
PCT/EP2020/062813 WO2020229329A1 (en) | 2019-05-10 | 2020-05-08 | Use of 2-phenyl-6-(1h-imidazol-1-yl)quinazoline for treating neurodegenerative diseases, preferably alzheimer's disease |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113811304A true CN113811304A (zh) | 2021-12-17 |
Family
ID=66483909
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202080034767.XA Pending CN113811304A (zh) | 2019-05-10 | 2020-05-08 | 2-苯基-6-(1h-咪唑-1-基)喹唑啉用于治疗神经退行性疾病,优选阿尔茨海默病的用途 |
Country Status (6)
Country | Link |
---|---|
US (2) | US20220257598A1 (zh) |
EP (2) | EP3735974A1 (zh) |
JP (1) | JP2022540286A (zh) |
CN (1) | CN113811304A (zh) |
ES (1) | ES2931104T3 (zh) |
WO (1) | WO2020229329A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115429782A (zh) * | 2022-07-20 | 2022-12-06 | 中国科学院动物研究所 | 乙酸盐在制备预防或治疗神经***发育障碍药物中的应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004000312A2 (de) * | 2002-06-19 | 2003-12-31 | Solvay Pharmaceuticals Gmbh | Arzneimittel zur behandlung von eine inhibition oder aktivitätsverminderung von ph-wert-regulierenden bikarbonat-transporter-proteinen erfordernden erkrangungen |
CN102159208A (zh) * | 2008-06-20 | 2011-08-17 | 罗塔药品股份有限公司 | 6-1h-咪唑-1-基喹唑啉和喹啉衍生物、新的mao抑制剂和咪唑啉受体配体 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080004332A1 (en) | 2002-03-07 | 2008-01-03 | Alkon Daniel L | Methods for alzheimer's disease treatment and cognitive enhancement |
PT2066653E (pt) * | 2006-08-03 | 2012-10-22 | Rottapharm Spa | Derivados de 6-1h-imidazo-quinazolina e quinolinas, novos potentes analgésicos e agentes anti-inflamatórios |
IT1395963B1 (it) | 2009-06-04 | 2012-11-02 | Rottapharm Spa | Forme cristalline di 6-(1h-imidazol-1-il)-2-fenil chinazolina e dei suoi sali |
CA2906164A1 (en) | 2013-03-15 | 2014-09-18 | Daniel L. Alkon | Methods for identifying neuroprotective pkc activators |
-
2019
- 2019-05-10 EP EP19173783.2A patent/EP3735974A1/en not_active Withdrawn
-
2020
- 2020-05-08 CN CN202080034767.XA patent/CN113811304A/zh active Pending
- 2020-05-08 ES ES20729634T patent/ES2931104T3/es active Active
- 2020-05-08 WO PCT/EP2020/062813 patent/WO2020229329A1/en unknown
- 2020-05-08 US US17/610,054 patent/US20220257598A1/en not_active Abandoned
- 2020-05-08 EP EP20729634.4A patent/EP3965769B1/en active Active
- 2020-05-08 JP JP2021566936A patent/JP2022540286A/ja active Pending
-
2023
- 2023-11-07 US US18/387,577 patent/US20240091227A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004000312A2 (de) * | 2002-06-19 | 2003-12-31 | Solvay Pharmaceuticals Gmbh | Arzneimittel zur behandlung von eine inhibition oder aktivitätsverminderung von ph-wert-regulierenden bikarbonat-transporter-proteinen erfordernden erkrangungen |
CN102159208A (zh) * | 2008-06-20 | 2011-08-17 | 罗塔药品股份有限公司 | 6-1h-咪唑-1-基喹唑啉和喹啉衍生物、新的mao抑制剂和咪唑啉受体配体 |
Non-Patent Citations (1)
Title |
---|
CHRISTIAN GRINÁN-FERRÉ等: "Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice", NEUROTHERAPEUTICS, vol. 16, no. 2, 20 November 2018 (2018-11-20), pages 416 - 431 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115429782A (zh) * | 2022-07-20 | 2022-12-06 | 中国科学院动物研究所 | 乙酸盐在制备预防或治疗神经***发育障碍药物中的应用 |
CN115429782B (zh) * | 2022-07-20 | 2024-03-29 | 中国科学院动物研究所 | 乙酸盐在制备预防或治疗神经***发育障碍药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
EP3965769A1 (en) | 2022-03-16 |
US20220257598A1 (en) | 2022-08-18 |
EP3735974A1 (en) | 2020-11-11 |
JP2022540286A (ja) | 2022-09-15 |
EP3965769B1 (en) | 2022-09-07 |
ES2931104T3 (es) | 2022-12-27 |
WO2020229329A1 (en) | 2020-11-19 |
US20240091227A1 (en) | 2024-03-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6133790B2 (ja) | ミエリン形成細胞運命へのオリゴデンドロサイト前駆細胞の定方向分化 | |
Kabogo et al. | β-amyloid-related peptides potentiate K+-evoked glutamate release from adult rat hippocampal slices | |
Lauterbach | An extension of hypotheses regarding rapid-acting, treatment-refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan | |
ES2340708T3 (es) | Tratamiento de esclerosis lateral amiotrofica con pirimetamina y analogos. | |
Soudy et al. | Cyclic AC253, a novel amylin receptor antagonist, improves cognitive deficits in a mouse model of Alzheimer's disease | |
US20150322049A1 (en) | Leukotriene pathway antagonists for the treatment of dementia, cognitive deficits in parkinson's disease and/or learning and memory deficiencies in parkinson's disease | |
US20220193053A1 (en) | Cystic fibrosis transmembrane conductance regulator modulators for treating autosomal dominant polycystic kidney disease | |
US20240091227A1 (en) | Use Of 2-Phenyl-6-(1H-Imidazol-1-YL) Quinazoline For Treating Neurodegenerative Diseases, Preferably Alzheimer's Disease | |
Raman et al. | Chemokines, macrophage inflammatory protein-2 and stromal cell-derived factor-1α, suppress amyloid β-induced neurotoxicity | |
US20130266663A1 (en) | Sox9 inhibitors | |
Ding et al. | Increased expression of HERPUD1 involves in neuronal apoptosis after intracerebral hemorrhage | |
Cheng et al. | DRD1 agonist A-68930 improves mitochondrial dysfunction and cognitive deficits in a streptozotocin-induced mouse model | |
EP3429671B1 (en) | COMPOSITION AND METHODS FOR STIMULATING CLEARANCE OF AMYLOID-ß PROTEIN | |
CN107921105B (zh) | Il-8抑制剂用于治疗某些泌尿疾病的用途 | |
EP3949974A1 (en) | Composition for preventing or treating neuroinflammatory disorders, comprising bee venom extract as active ingredient | |
Liu et al. | A Novel multifunctional 5, 6-dimethoxy-indanone-chalcone-carbamate hybrids alleviates cognitive decline in Alzheimer’s disease by dual inhibition of acetylcholinesterase and inflammation | |
US11179358B2 (en) | Compound for use in the prevention and treatment of neurodegenerative diseases | |
WO2018136933A1 (en) | Inhibition of stromal interaction molecule 1 (stim1) as a co-treatment for adult onset polycystic kidney disease (adpkd) | |
US20220133702A1 (en) | Cystic fibrosis transmembrane conductance regulator modulators for treating autosomal dominant polycystic kidney disease | |
EP4093395B1 (en) | Eletriptan hydrobromide for treatment of spinal cord injury and improvement of locomotor function | |
AU2022311958A1 (en) | Inhibitors of amyloid beta oligomerization and therapeutic uses thereof | |
EP3207925A1 (en) | Compound for use in the prevention and treatment of neurodegenerative diseases | |
Cassano et al. | Preclinical progress with CHF2819, a novel orally active acetylcholinesterase inhibitor | |
CN113365619A (zh) | 成胶质细胞瘤的治疗和预防 | |
CN114929217A (zh) | 基于ampk抑制功能和锌稳态控制功能用于治疗多发性硬化的药物组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |