GB2447791A - Pharmaceutical formulations and compounds for use in alleviating conditions related to Down's syndrome - Google Patents
Pharmaceutical formulations and compounds for use in alleviating conditions related to Down's syndrome Download PDFInfo
- Publication number
- GB2447791A GB2447791A GB0805357A GB0805357A GB2447791A GB 2447791 A GB2447791 A GB 2447791A GB 0805357 A GB0805357 A GB 0805357A GB 0805357 A GB0805357 A GB 0805357A GB 2447791 A GB2447791 A GB 2447791A
- Authority
- GB
- United Kingdom
- Prior art keywords
- alkyl
- hydrogen
- dashed line
- syndrome
- alkyloxycarbonyl
- 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.)
- Withdrawn
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 39
- 201000010374 Down Syndrome Diseases 0.000 title claims abstract description 31
- 206010044688 Trisomy 21 Diseases 0.000 title claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- BXNJHAXVSOCGBA-UHFFFAOYSA-N Harmine Chemical compound N1=CC=C2C3=CC=C(OC)C=C3NC2=C1C BXNJHAXVSOCGBA-UHFFFAOYSA-N 0.000 claims abstract description 18
- RHVPEFQDYMMNSY-UHFFFAOYSA-N harmalol Chemical compound N1C2=CC(O)=CC=C2C2=C1C(C)=NCC2 RHVPEFQDYMMNSY-UHFFFAOYSA-N 0.000 claims abstract description 14
- RERZNCLIYCABFS-UHFFFAOYSA-N Harmaline hydrochloride Natural products C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 claims abstract description 13
- PSFDQSOCUJVVGF-UHFFFAOYSA-N harman Chemical compound C12=CC=CC=C2NC2=C1C=CN=C2C PSFDQSOCUJVVGF-UHFFFAOYSA-N 0.000 claims abstract description 12
- VJHLDRVYTQNASM-UHFFFAOYSA-N harmine Natural products CC1=CN=CC=2NC3=CC(=CC=C3C=21)OC VJHLDRVYTQNASM-UHFFFAOYSA-N 0.000 claims abstract description 9
- 208000024891 symptom Diseases 0.000 claims abstract description 6
- 238000009472 formulation Methods 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- -1 alkylthjo Chemical group 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000004615 ingredient Substances 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 239000002245 particle Substances 0.000 claims description 5
- 230000002685 pulmonary effect Effects 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 230000000069 prophylactic effect Effects 0.000 claims description 4
- 230000003400 hallucinatory effect Effects 0.000 claims description 3
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- 230000002500 effect on skin Effects 0.000 claims description 2
- 238000007918 intramuscular administration Methods 0.000 claims description 2
- 238000001990 intravenous administration Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- 150000003863 ammonium salts Chemical class 0.000 claims 1
- 230000007812 deficiency Effects 0.000 abstract description 5
- 102100028554 Dual specificity tyrosine-phosphorylation-regulated kinase 1A Human genes 0.000 abstract description 4
- 101000838016 Homo sapiens Dual specificity tyrosine-phosphorylation-regulated kinase 1A Proteins 0.000 abstract description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 17
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 15
- 108091000080 Phosphotransferase Proteins 0.000 description 14
- 102000020233 phosphotransferase Human genes 0.000 description 14
- 238000003556 assay Methods 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- 239000007983 Tris buffer Substances 0.000 description 10
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 10
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 9
- 235000011285 magnesium acetate Nutrition 0.000 description 9
- 239000011654 magnesium acetate Substances 0.000 description 9
- 229940069446 magnesium acetate Drugs 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 108010011376 AMP-Activated Protein Kinases Proteins 0.000 description 6
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 description 6
- 108010069682 CSK Tyrosine-Protein Kinase Proteins 0.000 description 6
- 102000052052 Casein Kinase II Human genes 0.000 description 6
- 108010010919 Casein Kinase II Proteins 0.000 description 6
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 102100034069 MAP kinase-activated protein kinase 2 Human genes 0.000 description 6
- 101710141394 MAP kinase-activated protein kinase 2 Proteins 0.000 description 6
- 102000056243 Mitogen-activated protein kinase 12 Human genes 0.000 description 6
- 102000056248 Mitogen-activated protein kinase 13 Human genes 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 102100031167 Tyrosine-protein kinase CSK Human genes 0.000 description 6
- 239000003112 inhibitor Substances 0.000 description 6
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 6
- 101000578774 Homo sapiens MAP kinase-activated protein kinase 5 Proteins 0.000 description 5
- 102100028396 MAP kinase-activated protein kinase 5 Human genes 0.000 description 5
- 101150003567 Mapk12 gene Proteins 0.000 description 5
- 101150060694 Mapk13 gene Proteins 0.000 description 5
- 108700036166 Mitogen-Activated Protein Kinase 11 Proteins 0.000 description 5
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 5
- 102100026929 Mitogen-activated protein kinase 11 Human genes 0.000 description 5
- 108700015929 Mitogen-activated protein kinase 12 Proteins 0.000 description 5
- 108700015928 Mitogen-activated protein kinase 13 Proteins 0.000 description 5
- 102100035044 Myosin light chain kinase, smooth muscle Human genes 0.000 description 5
- 101100202399 Oryza sativa subsp. japonica SAPK4 gene Proteins 0.000 description 5
- 101150105578 SAPK3 gene Proteins 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000006735 deficit Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000011534 wash buffer Substances 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 4
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 4
- 101000945096 Homo sapiens Ribosomal protein S6 kinase alpha-5 Proteins 0.000 description 4
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 4
- 101000691459 Homo sapiens Serine/threonine-protein kinase N2 Proteins 0.000 description 4
- 101001047681 Homo sapiens Tyrosine-protein kinase Lck Proteins 0.000 description 4
- 108700012928 MAPK14 Proteins 0.000 description 4
- 102000054819 Mitogen-activated protein kinase 14 Human genes 0.000 description 4
- 101710198035 Myosin light chain kinase, smooth muscle Proteins 0.000 description 4
- 101150020891 PRKCA gene Proteins 0.000 description 4
- 102000001253 Protein Kinase Human genes 0.000 description 4
- 102100033645 Ribosomal protein S6 kinase alpha-5 Human genes 0.000 description 4
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 4
- 102100026180 Serine/threonine-protein kinase N2 Human genes 0.000 description 4
- 102100024036 Tyrosine-protein kinase Lck Human genes 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 230000003340 mental effect Effects 0.000 description 4
- 235000011007 phosphoric acid Nutrition 0.000 description 4
- 108060006633 protein kinase Proteins 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 102100037263 3-phosphoinositide-dependent protein kinase 1 Human genes 0.000 description 3
- 102000000584 Calmodulin Human genes 0.000 description 3
- 108010041952 Calmodulin Proteins 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
- 101001059429 Homo sapiens MAP/microtubule affinity-regulating kinase 3 Proteins 0.000 description 3
- 101000628949 Homo sapiens Mitogen-activated protein kinase 10 Proteins 0.000 description 3
- 101000976899 Homo sapiens Mitogen-activated protein kinase 15 Proteins 0.000 description 3
- 101000588540 Homo sapiens Serine/threonine-protein kinase Nek6 Proteins 0.000 description 3
- 101000588545 Homo sapiens Serine/threonine-protein kinase Nek7 Proteins 0.000 description 3
- 101001001648 Homo sapiens Serine/threonine-protein kinase pim-2 Proteins 0.000 description 3
- 102100028397 MAP kinase-activated protein kinase 3 Human genes 0.000 description 3
- 101710141393 MAP kinase-activated protein kinase 3 Proteins 0.000 description 3
- 102100033610 MAP kinase-interacting serine/threonine-protein kinase 2 Human genes 0.000 description 3
- 101710138999 MAP kinase-interacting serine/threonine-protein kinase 2 Proteins 0.000 description 3
- 102100028920 MAP/microtubule affinity-regulating kinase 3 Human genes 0.000 description 3
- 102100026931 Mitogen-activated protein kinase 10 Human genes 0.000 description 3
- 102100023483 Mitogen-activated protein kinase 15 Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 108090000315 Protein Kinase C Proteins 0.000 description 3
- 102000003923 Protein Kinase C Human genes 0.000 description 3
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 3
- 102100033643 Ribosomal protein S6 kinase alpha-3 Human genes 0.000 description 3
- 102100037628 Serine/threonine-protein kinase 3 Human genes 0.000 description 3
- 102100031400 Serine/threonine-protein kinase Nek7 Human genes 0.000 description 3
- 102100036120 Serine/threonine-protein kinase pim-2 Human genes 0.000 description 3
- 239000005441 aurora Substances 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000012139 lysis buffer Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- KJAXEBRGQOHHOY-VXRVIWLSSA-N (4s)-4-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s,3r)-2-[[(2s)-2-[[(2s)-1-[(2s)-2-[(2-aminoacetyl)amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropan Chemical compound N([C@@H](CCCN=C(N)N)C(=O)N[C@@H]([C@H](O)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(O)=O)C(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)CN KJAXEBRGQOHHOY-VXRVIWLSSA-N 0.000 description 2
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 2
- 101001082110 Acanthamoeba polyphaga mimivirus Eukaryotic translation initiation factor 4E homolog Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108010026870 Calcium-Calmodulin-Dependent Protein Kinases Proteins 0.000 description 2
- 102000019025 Calcium-Calmodulin-Dependent Protein Kinases Human genes 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102000005636 Cyclic AMP Response Element-Binding Protein Human genes 0.000 description 2
- 108010045171 Cyclic AMP Response Element-Binding Protein Proteins 0.000 description 2
- 108010068192 Cyclin A Proteins 0.000 description 2
- 102100025191 Cyclin-A2 Human genes 0.000 description 2
- 102100023114 Dual specificity tyrosine-phosphorylation-regulated kinase 3 Human genes 0.000 description 2
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 2
- 102000001267 GSK3 Human genes 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 description 2
- 101001049991 Homo sapiens Dual specificity tyrosine-phosphorylation-regulated kinase 3 Proteins 0.000 description 2
- 101000945090 Homo sapiens Ribosomal protein S6 kinase alpha-3 Proteins 0.000 description 2
- 101000826081 Homo sapiens SRSF protein kinase 1 Proteins 0.000 description 2
- 101000880439 Homo sapiens Serine/threonine-protein kinase 3 Proteins 0.000 description 2
- 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 2
- 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 description 2
- 101150057269 IKBKB gene Proteins 0.000 description 2
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 102100026299 MAP kinase-interacting serine/threonine-protein kinase 1 Human genes 0.000 description 2
- 101710139011 MAP kinase-interacting serine/threonine-protein kinase 1 Proteins 0.000 description 2
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 2
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 108091008611 Protein Kinase B Proteins 0.000 description 2
- 102000001332 SRC Human genes 0.000 description 2
- 102100023010 SRSF protein kinase 1 Human genes 0.000 description 2
- 229920002684 Sepharose Polymers 0.000 description 2
- 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 2
- 102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 108010024505 crosstide peptide Proteins 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 239000006167 equilibration buffer Substances 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 229940100662 nasal drops Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 2
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 108010056274 polo-like kinase 1 Proteins 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000007493 shaping process Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 108010082078 3-Phosphoinositide-Dependent Protein Kinases Proteins 0.000 description 1
- 102000019050 90-kDa Ribosomal Protein S6 Kinases Human genes 0.000 description 1
- 108010012196 90-kDa Ribosomal Protein S6 Kinases Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 101150012716 CDK1 gene Proteins 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- 102100023033 Cyclic AMP-dependent transcription factor ATF-2 Human genes 0.000 description 1
- 102000004654 Cyclic GMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010003591 Cyclic GMP-Dependent Protein Kinases Proteins 0.000 description 1
- 101001082109 Danio rerio Eukaryotic translation initiation factor 4E-1B Proteins 0.000 description 1
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 1
- 101001031598 Dictyostelium discoideum Probable serine/threonine-protein kinase fhkC Proteins 0.000 description 1
- 108700001011 Drosophila mnb Proteins 0.000 description 1
- 102100023115 Dual specificity tyrosine-phosphorylation-regulated kinase 2 Human genes 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000000564 Elongation Factor 2 Kinase Human genes 0.000 description 1
- 108010016831 Elongation Factor 2 Kinase Proteins 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 101000600890 Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139) G2-specific protein kinase nimA Proteins 0.000 description 1
- 101100059559 Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139) nimX gene Proteins 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 108060006662 GSK3 Proteins 0.000 description 1
- 108091007911 GSKs Proteins 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 1
- 102000004103 Glycogen Synthase Kinases Human genes 0.000 description 1
- 101000974934 Homo sapiens Cyclic AMP-dependent transcription factor ATF-2 Proteins 0.000 description 1
- 101001049990 Homo sapiens Dual specificity tyrosine-phosphorylation-regulated kinase 2 Proteins 0.000 description 1
- 101000877727 Homo sapiens Forkhead box protein O1 Proteins 0.000 description 1
- 101000997829 Homo sapiens Glial cell line-derived neurotrophic factor Proteins 0.000 description 1
- 101000945272 Homo sapiens Phosphorylase b kinase regulatory subunit alpha, liver isoform Proteins 0.000 description 1
- 102000019145 JUN kinase activity proteins Human genes 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 239000007993 MOPS buffer Substances 0.000 description 1
- 206010027374 Mental impairment Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100040243 Microtubule-associated protein tau Human genes 0.000 description 1
- 101710115937 Microtubule-associated protein tau Proteins 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 108010074596 Myosin-Light-Chain Kinase Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 108010058765 Oncogene Protein pp60(v-src) Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 101000822645 Oryza sativa subsp. japonica Serine/threonine-protein kinase SAPK3 Proteins 0.000 description 1
- 101001092938 Oryza sativa subsp. japonica Serine/threonine-protein kinase SAPK4 Proteins 0.000 description 1
- 240000005523 Peganum harmala Species 0.000 description 1
- 235000005126 Peganum harmala Nutrition 0.000 description 1
- 108010044843 Peptide Initiation Factors Proteins 0.000 description 1
- 102000005877 Peptide Initiation Factors Human genes 0.000 description 1
- 102000014750 Phosphorylase Kinase Human genes 0.000 description 1
- 108010064071 Phosphorylase Kinase Proteins 0.000 description 1
- 102100033548 Phosphorylase b kinase regulatory subunit alpha, liver isoform Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 108010034782 Ribosomal Protein S6 Kinases Proteins 0.000 description 1
- 102000009738 Ribosomal Protein S6 Kinases Human genes 0.000 description 1
- 101710146185 Ribosomal protein S6 kinase 2 alpha Proteins 0.000 description 1
- 108091006629 SLC13A2 Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 101710202847 Serine/threonine-protein kinase 3 Proteins 0.000 description 1
- 102100031401 Serine/threonine-protein kinase Nek6 Human genes 0.000 description 1
- 101100273808 Xenopus laevis cdk1-b gene Proteins 0.000 description 1
- 241000159213 Zygophyllaceae Species 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- SFNALCNOMXIBKG-UHFFFAOYSA-N ethylene glycol monododecyl ether Chemical compound CCCCCCCCCCCCOCCO SFNALCNOMXIBKG-UHFFFAOYSA-N 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 210000003917 human chromosome Anatomy 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 108010085212 mitogen and stress-activated protein kinase 1 Proteins 0.000 description 1
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 108010036962 polypeptide 3 90kDa ribosomal protein S6 kinase Proteins 0.000 description 1
- 208000000170 postencephalitic Parkinson disease Diseases 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FRGKKTITADJNOE-UHFFFAOYSA-N sulfanyloxyethane Chemical compound CCOS FRGKKTITADJNOE-UHFFFAOYSA-N 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Pharmaceutical formulation of compound (I) may be useful in alleviating or minimising a symptom or condition observed in a Down's syndrome subject. Compound (I) may be harmine, harmaline, harmane or harmalol. The compounds may act on protein kinase DYRK / DYRK1a and may be useful to treat learning deficiencies associated with Down's syndrome. <EMI ID=1.1 HE=52 WI=70 LX=369 LY=1290 TI=CF>
Description
1 2447791 METHOD OF TREATING LEARNING IMPAIRMENT IN DOWN'S
SYNDROME SUBJECTS
Field of the Invention
The present invention provides compounds for use and methods of alleviating learning and/or mental impairment in people suffering from Down's syndrome.
Background to the Invention
People with Down's syndrome have an extra chromosome (number 21) in some or all of their cells. This results in physical and mental characteristics which often includes learning difficulties, common facial features and heart problems.
Approximately I in 1000 children born in the UK are affected by Down's syndrome.
Children with Down's syndrome usually learn to walk, talk, read and write, but more slowly than other children of their age and ultimate IQ is generally below average.
Screening tests are available that can assist parents to assess the risk of their unborn child having Down's syndrome and some parents may decide to terminate the pregnancy if their baby has Down's syndrome.
Babies with Down's syndrome are usually diagnosed in the first few days after birth. However, there are currently no drug therapies for alleviating symptoms, such as the mental and learning impairment associated with Down's syndrome.
An object of the present invention is to obviate and/or mitigate mental and/or learning impairment in people with Down's syndrome.
A further object of the invention is to provide compounds suitable for use in children with Down's syndrome to help treat the mental and/or learning impairment associated with Down's syndrome.
The present invention is based in part on work carried out by the present inventors in relation to the protein kinase DYRKIa (Woods YL, Rena G, Morrice N, Barthel A, Becker W, Guo S, Unterman TG, Cohen P. Biochem. J. 2001, 355, 597-607 The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site; Woods YL, Cohen P, Becker W, Jakes R, Goedert M, Wang X, Proud CG. Biochem. J. 2001, 355, 609-615 The kinase DYRJ( 1 A phosphorylates protein-synthesis initiation factor eIF2Bc at Ser 539 and the microtubule-associated protein tau at Thr 212: potential role for DYRK as a glycogen synthase kinase 3-priming kinase). Since those with Down's tend to have a problem converting phenylalanine into tyrosine, it is possible that DYRJ( (dual-specificity tyrosine -regulated kinase) may have some involvement in regulating this reaction. Moreover, DYRK1a is known to map to the "Down's syndrome critical region"(Gujmera J, Casas C, Pucharos C, Solans A, Domenech A, Planas AM, Ashley J, Lovett M, Estivill X, Pritchard M. Hum Mol Genet.
1996, 5, 1305-13 10. A human homologue of Drosophila minibrain (MNB) is expressed in neuronal regions affected in Down syndrome and maps to the critical region) and animals over-expressing DYR.Kla have learning and memory deficiencies. (Smith Di, Stevens ME, Sudanagunta SP, Bronson RT, Makhirison M, Watabe AM, O'Dell Ti, Fung J, Weier HU, Cheng iF, Rubin EM. Nat Genet.
1997,16(1):8-9. Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome) and may therefore be seen as a possible target for treating learning deficiencies associated with Downs.
In a first aspect there is provided use of a compound or salt or hydroxide thereof of the following formula (I) R3/ wherein R1 is selected from hydrogen; substituted or unsubstituted C1-C6 alkyl, alkenyl, or alkyloxy, alkylthio, alkyloxycarbonyl; hydroxyl; nitro; amino; halo or oxo; R2 and R3 are independently selected from hydrogen; substituted or unsubstituted C1-C6 alkyl, alkenyl, or alkyloxy, alkylthio, alkyloxycarbonyl; hydroxyl; nitro; amino or halo; and R4 is selected from hydrogen; substituted or unsubstituted C1-C6 alkyl, alkenyl, or alkyloxycarbonyl; the dashed line represents a single or double bond, for the manufacture of a medicament for alleviating or minimising a symptom or condition observed in a Down's syndrome subject.
Typically the compound is used to improve and/or alleviate deficiencies in learning as experienced by subjects with Down's syndrome. Generally, Down's syndrome subjects are born with a brain capacity (IQ) similar to subjects without Down's syndrome, but as they grow, Down's syndrome subjects generally display a slower andlor reduced learning capacity such that by age 13, Down's syndrome subjects display a mean IQ below 50. It is envisaged therefore that the compounds of the present invention may be administered to a Down's syndrome subject from birth, or soon thereafter, until adolescence or possibly into and during adulthood.
In a further aspect there is provided a method of treating or preventing a learning impairment or deficiency in a subject suffering from Down's syndrome, the method comprising administering to the Down's syndrome subject a compound or salt or hydroxide thereof of the following formula (I) R3/ wherein R1, R2, R3 and R4 and the dashed line have the same meanings as given herein above.
The above method may generally be practised on Down's syndrome subjects from birth to adolescence.
Preferably R1, R2 and R3 are independently selected from hydrogen, hydroxyl or C1-C6 alkyl or alkyloxy; and R4 is selected from hydrogen or C1-C6 alkyl.
Typical salts may be formed by preparing a quaternary ammonium salt at one or more of the nitrogen atoms. For example, reaction with an inorganic or organic acid may be used to protonate the nitrogen atom to provide a positively charged nitrogen which is charge balanced with an anion species. Similarly, a hydroxide derivative may be provided by reaction with water.
Particularly preferred compounds are: Harmine, where R1 is H, R2 is CH3, R3 is OCH3, R1 is H and the dashed line is a double bond; Harmaljne, where R1 is H, R2 is CH3, R3 is OCH3, R4 is H and the dashed line is a single bond; Harmane, where R1 is H, R2 is CH3, R3 is H, R4 is H and the dashed line is a double bond; and Harmalol, where R1 is H, R2 is CH3, R3 is OH, R4 is H and the dashed line is a single bond.
Harmine is an alkaloid from seeds of Peganum harmala L., Zygophyllaceae. It is an active ingredient of hallucinogenic drinks made in the western Amazon region from related plants. There is no known therapeutic use but it was suggested to be a cure for postencephalitic Parkinson disease in the 1920's.
For use according to the present invention, the compounds or physiologically acceptable salt, hydroxide or other physiologically functional derivative thereof described herein may be presented as a pharmaceutical formulation, comprising the compound or physiologically acceptable salt, hydroxide or other physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic andlor prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical formulations include those suitable for oral, topical (including dermal, buccal and sublingual), rectal or parenteral (including subcutaneous, intraderrnal, intramuscular and intravenous), nasal and pulmonary administration e.g., by inhalation. The formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Pharmaceutical formulations suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent. Moulded tablets may be made by moulding an active compound with an inert liquid diluent.
Tablets may be optionally coated and, if uncoated, may optionally be scored.
Capsules may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner. Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope. An active compound may also be formulated as dispersable granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet. Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.
Formulations for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release -controlling matrix, or is coated with a suitable release -controlling film.
Such formulations may be particularly convenient for prophylactic use.
Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials comnionly used in the art. The suppositories may be conveniently formed by admixture of an active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.
Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles.
Injectible preparations may be adapted for bolus injection or Continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use. Alternatively, an active compound may be in powder form which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.
An active compound may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use.
Formulations suitable for pulmonary administration the buccal cavity are presented such that particles containing an active compound and desirably having a diameter in the range of 0.5 to 7 microns are delivered in the bronchial tree of the recipient.
As one possibility such formulations are in the form of finely comminuted powders which may conveniently be presented either in a pierceable capsule, suitably of, for example, gelatin, for use in an inhalation device, or alternatively as a self-propelling formulation comprising an active compound, a suitable liquid or gaseous propellant and optionally other ingredients such as a surfactarit and/or a solid diluent. Suitable liquid propellants include propane and the chiorofluorocarbons, and suitable gaseous propellarits include carbon dioxide.
Self-propelling formulations may also be employed wherein an active compound is dispensed in the form of droplets of solution or suspension.
Such self-propelling formulations are analogous to those known in the art and may be prepared by established procedures. Suitably they are presented in a container provided with either a manually-operable or automatically functioning valve having the desired spray characteristics; advantageously the valve is of a metered type delivering a fixed volume, for example, 25 to 100 microlitres, upon each operation thereof.
As a further possibility an active compound may be in the form of a solution or suspension for use in an atomizer or nebuliser whereby an accelerated airstream or ultrasonic agitation is employed to produce a fine droplet mist for inhalation.
Formulations suitable for nasal administration include preparations generally similar to those described above for pulmonary administration. When dispensed such formulations should desirably have a particle diameter in the range to 200 microns to enable retention in the nasal cavity; this may be achieved by, as appropriate, use of a powder of a suitable particle size or choice of an appropriate valve. Other suitable formulations include coarse powders having a particle diameter in the range 20 to 500 microns, for administration by rapid inhalation through the nasal passage from a container held close up to the nose, and nasal drops comprising 0.2 to 5% w/v of an active compound in aqueous or oily solution or suspension.
It should be understood that in addition to the aforementioned carrier ingredients the pharmaceutical formulations described above may include, an appropriate one or more additional carrier ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents aie propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
Dosages of the compounds of the present invention include those sufficient to provide the benefical effects for alleviating or minimising a symptom or condition observed in a Down's syndrome subject, whilst not eliciting an hallucinogenic effect on the subject.
Detailed description
Materials and Methods Kinase assays All assays (25.5111) were carried out at room temperature (21 C) and were linear with respect to time and enzyme concentrations under the conditions used.
Assays were performed for 30 minutes except assays for LCK and PKB which were performed for 15 minutes using Multidrop Micro reagent dispensers (Thermo Electron Corporation, Waltham, MA 02454, USA) in a 96-well format.
The concentration of magnesium acetate and [T-33P] ATP (800cpmlpmol) in the assays was one of three concentrations (5, 20 or 50.tM) in order to be at or below Km for ATP for the enzyme. Assays were initiated with MgATP and stopped by addition of of 0.5M orthophosphoric acid. Assays were then harvested Onto P81 filterplates using a unifilter harvester (PerkinElmer, Boston, MA 02118, USA), with a wash buffer of 50 mM orthophosphoric acid. Filterplates were then air dried overnight. I 0tl of Microscint 0 was added per well prior to counting for radioactivity.
MKKI, INKJSAPKIc, SAPK2a/p38, SAPK2b/p38j32, SAPK3/p38y, SAPK4/p38ö, MAPK2/ERJ(2, MAPKAP-K1j3, MAPKAP-K2, MSKI, PRAK, PKA, PKCa, PDKI, SGK, p7OS6K, GSK3I3, ROCK-Il, PRK2, AMPK, CHKI, CHK2, CK2, PHK, LCK, were assayed according to Davies et a!., (Davies, S.P., Reddy, H., Caivano, M. and Cohen, P. Biochem. J. 351, 95-105, 2000.
CSK and CDK2/cycljnA, were assayed according to Bain et al. (Bain J, McLauchlari 1-i, Elliott M, Cohen P. Biochem J. 371, 199-204, 2003., except that ATP concentrations were either 5,20 or 5Omicromolar so that they were at or below the Km for ATP. The ATP concentrations used were as follows, 5M for assays of MKKI, SAPK3, SAPK4, GSK3I3, PRK2 CK2 20j.im for assays of iNK, SAPK2f3, MAPKAP-K2, MSK1, PRAK, PKA, PKCa, PDKI, SGK, p7OS6K, ROCK-H, CHKI, CHK2, CSK, CDK2, and 5OpM for assays of SAPK2a, MAPK2IERK2, AMPK, LCK, P11K and MAPKAP-K1f3.
The following kinases were assayed against the substrates indicated.
Aurora B was assayed against the substrate peptide LRRLSLGLRRLSLGLRPJSLGLPJJSLG (300j.tM), ERK8 and MST-2 were both assayed against MBP (O.33mg/ml). IKK was assayed against the substrate peptide LDDRHDSGLDSMKDEEY (300i.tM), JNK3 was assayed against 3jtM ATF2[19-96J. MAPKAP-K3 and PKDI were both assayed against KKLNRTLSVA (30.tM), MARK3 was assayed against CI-IKtide (KKKVSRSGLYRSPSMpENLNppR) substrate peptide (300tM). MNK1 and MNK2 were both assayed against eIF4E protein (O.Smg/ml). NEK7 was assayed against FLAKSFGSPNRAyKK (300MM), PIM2 was assayed against RSRHSSYPAGT (300MM), L\PH PKB3-S474D was assayed against Crosstide (30MM), PLKI was assayed against ISDELMDATFADQEAKKK (300MM).
PRK2 was assayed against Long S6 peptide, KEAKEKRQEQIAKRRRLSSLRSTSKSGGSQK (30MM), RSK2 was assayed against KKLNRTLSVA (30MM), SRC was assayed against cdc2 peptide, KVEKIGEGTYGVVYK (300MM) and SRPK1 was assayed against peptide RSRSRSRSRSRSRSR (300MM). All enzymes were diluted in 50mM Tris/1-ICI pH 7.5, 0.1mM EGTA, 1mg/mi BSA, 0.1% 13-mercaptoethanol buffer and assayed in an incubation containing 50mM Tris/J-ICI pH7.5, 0.1mM EGTA, 0.1% J3-mercaptoethanol, CAMK-1 (5-2OmU) diluted in 50mM Tris/HCI p1-I 7.5, 0.1mM EGTA, 1mg/mi BSA, 0.1% 13-mercaptoethanoi is assayed against substrate peptide YLRRRLSDSNF in an incubation containing 50mM Tris/HCI pH7.5, 0.1mM EGTA, 0.5mM CaCI2, 0.3MM calmodulin, 0.1% f3-mercaptoethanoi, 3 00MM substrate peptide, 10mM magnesium acetate and 0.05mM [33P-T-ATP] (SOO-l000cpmlpmole). EF2K (5-2OmU) diluted in 50mM Hepes pH6.6, 0.1% f3-mercaptoethanol, 1mg/mi BSA is assayed against a substrate peptide RKKFGESKTKTKEFL in an incubation containing 50mM Hepes pH6.6, 0.2mM CaCI2, 0.3MM Calmodulin, 0.05% b-mercaptoethariol, 300MM substrate peptide, 10mM magnesium acetate and 0.05mM [33P-y-ATP] (500-1 000cpmIpmole).
smMLCK (5-2OmU) diluted in 50mM Hepes pH7.5, 0.1mM EGTA, 1 mg.mI BSA, 0.1% f-mercaptoethanol is assayed against substrate peptide KKRPQRATSNVFA in an incubation containing 50mM Hepes pH7.5, 0.1mM EGTA, 5mM CaCI2, 1OMM calmodulin, 300MM substrate peptide, 10mM magnesium acetate and 0.05mM [33P-7-ATP] (500-1 000cpmlpmole).
MAPKAP-Kla (5-2OmU diluted in 20mM MOPS pH 7.5, 1mM EDTA, 0.01% Brij35, 5% glycerol, 0.1% 13-mercaptoethanoj, 1mg/mi BSA) is assayed against KKLNRTLSVA in a final volume of 25.5.il containing 50 mM Na-J3-glycerophosphate pH 7.5, 0.5mM EDTA, 30 MM substrate peptide, 10mM magnesium acetate and 0.05 mM {33P-j'ATPJ (50-1000 cpmlpmole) and incubated for 40 mm at room temperature.
NEK6 (5-20 mU diluted in 50mM Tris (p1-I 7.5), 0.1mM EGTA, 1mg/mi BSA, 0.1 %,3-Mercaptoethano1) is assayed against NEK6 peptide (FLAKSFGSPNPJYJ(JQ in a final volume of 25.Sj.tl containing 50mM Iris (pH 7.5), 0.1mM EGTA, 0.01% Brij, 0.1%, P-Mercaptoethanol, NEK6 peptide (0.3mM), 10mM magnesium acetate and 0.05mM [33P-ATP](5OO-1000 cpm/pmole) and incubated for 30 mm at room temperature.
5-2OmU of NEK2a (diluted in 50mM Tris (pH 7.5), 0.1mM EGTA, 1mg/mi BSA, 0.1 %,-Mercaptoethano1) is assayed against NEK2a peptide (RFRRSRRMI) in a final volume of 25.5j.ti containing 50mM Iris (pH 7.5), 0.1mM EGTA, 0.01% Brij, 0.1%, 13-Mercaptoethanoz, 300MM NEK2a peptide, 10 mM magnesium acetate and 0.05 mM {33P-ATPJ(5oo-1ooo cpm/pmole) and incubated for 30 mins at room temperature.
IWH-PKBbeta-5474D (5-2OmU diluted in 50 mM Tris pH 7.5, 0.1 mM EGTA, 0.1% 13-mercaptoethanoj, 1 mg/mI BSA) is assayed against a modified Crosstide peptide (GRPRTSSFAEG}cJ() in a final volume of 25.5 M1 containing 50mM Tris pH 7.5, 0.05% 13-mercaptoethanol 30 MM substrate peptide, 10 mM magnesium acetate and 0.05 mM [33P-ATP] (50-1000 cpnilpmole) and incubated for 30 mm at room temperature.
Abbreviations Abbreviations used: AMPK, AMP-activated protein kinase; CAM-K, calmodulin-dependent protein kinase; CHK, checkpoint kinase; CK2, casein kinase 2; CREB, CAMP-response element binding protein; CSK, C-terminal Src kinase; DYRK, dual-specificity, tyrosine-phosphorylated and regulated kinase; EF2K elongation factor 2 kinase; EGF, epidermal growth factor; eIF4E eukaryotic initiation factor 4E; ERK, extracellular-signal-regujated kinase; GSK3, glycogen synthase kinase 3; IKKI3.j kappa B kinase; JNK, c-Jun N-terminal kinase; LCK, lymphocyte kinase; MAPK, mitogen-activated protein kinase; MAPKAP-K1, MAPK-activated protein kinase-1; MAPKAP-K2, MAPK-activated protein kinase 2; MKK, MAPK kinase (also called MEK); MLCK, myosin light chain kinase; MNK, MAPK-integrating kinase; MSK1, mitogen-and stress-activated protein kinase 1; NEK, never in mitosis gene a related protein kinase; PDK1, 3-phosphoinositide-dependent protein kinase 1; PKA, CAMP-dependent protein kinase; PKB, protein kinase B (also called Akt); PKC, protein kinase C; PKG, cGMP-dependent protein kinase; PHK, phosphorylase kinase; PLK, polo-like kinase 1; PRAK, p38-regulatcd/activated kinase; PRK, protein kinase C-related protein kinase; ROCKII, Rho-dependent protein kinase II; RSK2, ribosomal S6 kinase 2;SAPK2a, stress-activated protein kinase 2a (also called p38); SAPK2b, stress-activated protein kinase 2b (also called p382); SAPK3, stress-activated protein kinase 3 (also called p38y); SAPK4, stress-activated protein kinase 4 (also called p38ö); SGK, serum-and gIucocorticoicf-jndue kinase; SRC, v-src sarcoma viral oncogene homologue kinase; SRPKI, serine arginine protein kinase 1; p7OS6K, p70 ribosomal protein S6 kinase; Sk, skeletal muscle; Sm, smooth muscle.
Example 1: Expression and purification of GST-DYRKIa Flasks containing 500 ml of LB ampicillin are inoculated with pGEX-DYRKIa and grown at 37 C until OD at 600 nm is between 0.4 -0.6. The culture was then induced with 100 M JPTG and grown for 14 hours at 26 C.
The culture was harvested by centrifligation at 4,200 rpm for 30 mins and the bacterial pellet resuspended in ice cold lysis buffer (1 5 ml per IL of harvested culture) containing Roche protease inhibitor tablets (one tablet per 25 ml of lysis buffer).
The sample was then sonicated on ice for 8 x 15 seconds bursts, before being centrifuged at 15,000 rpm for 30 mins.
The clarified lysate was then added to GSH-Sepharose (Pharamacia) [which had been equilibrated in equilibration buffer] and end over end mixed for minutes at 4 C.
The GSH-Sepharose was then washed with wash buffer until the OD at 595 nm was zero.
GST-DYRKIa was eluted from the resin using elution buffer and fractions containing protein are pooled and dialysed overnight into dialysis buffer.
Buffers for purification of GST-DYRX1a Lysis Buffer: 50 mM Tris/FICI pH7.5 150mM NaCJ 1% Triton 1 mM EDTA 1 mM EGTA 0.1% t3-Mercaptoethanol 0.2 mM PMSF 1 mM benzamidjne Equilibration Buffer/Wash Buffer: 50 mM Tris pH7.5 250 mM NaC1 0.03% Brij-35 0.1mM EGTA 0.1 % 3-Mercaptoethanol 0.2 mM PMSF 1 mM benzamidine Elution: Wash buffer + 20mM glutathione (re-pl-I to 7.5) Dialysis: 50mM TrisfHCl pH7.5 0.1mM EGTA 150mM NaCI 50% glycerol 0.03% Brij-35 0.07% 13-Mercaptoethanol 1mM Benzamjdine 0.1mM PMSF.
Example 2: Kinase inhibition assays DYRK1A 33P screening assay: DYRK1A (5 -20 mU of diluted in 50 mM Iris pH 7.5, 0.1 mM EGIA) was assayed against Woodtide (KKISGRLSPIMTEQ) in a final volume of 25.5.tl containing 50 mM Iris pH 7.5, 0.1 mM EGTA, 350 uM substrate peptide, 10 mM magnesium acetate and 0.5 pi inhibitor and incubated at room temperature for 5 mins, followed by the addition of 0.05 mM [33P-gamma-ATP] (50-1000 cpm/pmole) and incubated for 30 mins at room temperature. Assays were stopped by addition of 5 jtt of 0.5 M (3%) orthophosphoric acid then harvested onto P81 Unifilter plates with a wash buffer of 50 mM orthophosphoric acid. Filterplates were then air dried overnight. I 0il of Microscint 0 was added per well prior to counting for radioactivity.
DYR2 and DYRK3 were assayed in an analogous manner to that described above for DYRK1a.
Harmine, 1-larmaline, Harmane and Harmalol were tested at 1 M and 10 uM (in the assay).
Results are shown in Tables I and 2 where values represent the percent activity in relation to the activity obtained in the absence of inhibitor, can be seen that all three compounds are very specific and active at 10gM and that harmine is a very potent and specific inhibitor of DYRKIa and still shows a high degree of activity at a concentration of 1.tM.
1C50 values were also obtained for DYRK1a, 2 and 3 with harmine (ATP at 50gM) (i.e. the concentration of the inhibitor that is required to provide 50% inhibition of the enzyme. The results are as follows: DYRKIa 1C50 O.08itM DYRK2 1C50 O.9i.tM DYRK3 1C50 O.8p.tM.
The 1C50 values were calculated by using half log dilutions of inhibitor, starting at I OOtM..
TABLE I
Legend Activities are presented as a percentage of those obtained in control assays carried out in the absence of inhibitor
TABLE 1
Harmaljne Harmane Harmalol Harmjne Concentration iM) 1 +1-SE 1 +1-SE 1 +1-SE -1 +1-SE MKKI 4 5 97 3 92 7 -76 3 JNKJSAPK1c 99 -6 96 -4 87 2 85 11 JNK3 8' 3 75 2 92 5 89 ______ SAPK2aJp38 89 6 95 5 95 _______ 95 5 SAPK2b/p3 8132 91 6 90 7 88 4 94 5 SAPK3/p38g 98 -0 108 4 98 9 82 -3 SAPK4/p38d 76 3 94 6 101 0 96 7 MAPK2/E1jç -80 2 86 7 88 3 98 2 ERK8 -58 2 39 3 41 2 25 1 MAPKAP-KJa 98 0 92 3 101 5 105 -6 MAPKAP-KIb 87 2 83_ 7 87 1 89 0 MAPKAP-K2 104 3 -114 -3 79 4 78 6 MAPKAP-K3 79 -3 85 3 95 1 89 -4 MSK1 98 ______ 5 98 1 84 3 90 ______ MNK1 I 89 6 871 O 8ü 1 84 -3 MNK2 88 0 75 9 97 6 84 0 PRAK 88 1 80 2 84 8 81 2 PKA 70 0 80 4 90 2 82 2 PKCa 88 2 84 1 109 0 96 0 PDK1 100 1 86 0 88 1 89 2 PKBtph 80 2 83 1 92 6 107 3 PKBb 97 3 92 6 103 3 94 1 SGK 14 1 98 2 62 4 66 1 CAMK-1 99 2 108 2 93 7 107 1 smMLCK 92 3 93 8 76 4 88 1 EFK2 106 9 96 3 97 9 102 1 70S6K 71 2 81 4 95 3 90 6 GSK3b 77 5 99 0 90 4 82 7 ROCK-H _____ 99 0 80 1 96 4 84 7 PRIQ 97 1 79 2 86 6 82 0 AMPK 97 3 75 5 92 1 98 1 CHK1 78 9 118 5 93 1 86 4 CHK2 89 0 89 4 76 5 78 6 CK1 84 2 82 1 83 1 61 4 CK2 94 4 96 3 55 7 82 8 PHK 73 9 94 6 101 ________O 103 5 Lel 77 4 92 5 85 2 92 2 CSK 64 3 92 1 110 2 92 1 Src 47 0 -106 0 101 0 108 2 CDK2/cyclin A 99 9 -110 3 9 5 98 5 DYRKIa 78 5 39 5 25 1 4 0 IEK2a 69 3 103 2 104 6 106 11 EK6 99 5 87 4 94 4 96 0 NEK7 95 3 -100 4 83 0 90 6 IKKb 78 1 90 7 93 1 97 8 PIM2 86 5 87 6 90 7 77 2 SRPK1 104 5 100 5 88 0 86 ________ Aurora B 98 0 98 1 110 3 100 9 MARK3 99 1 -108 5 93 7 86 1 MST2 98 4 116 5 85 5 91 5 PKD1 9 5 103 6 75 3 86 3 _____________________ 92 4 109 6 88 8 92 4
TABLE 2
Harmaljne Harmane Harmalol Harmine +1-SE 10 +1-SE 10 +1-SE 10 +1-SE MKKI 39 3 97 166 6 73 4 JNKJSAPK1c -96 3 72 3 84 6 69 7 JNK3 81 _______ 74 2 94 4 83 1 SAPK2aJp38 86 1 95 3 74 2 81 5 SAPK2b/p38f32 93 4 107 4 79 1 87 3 SAPK3/p38g 94 3 92 2 92 8 72 5 SAPK4/p38d 113 7 101 3 93 1 82 2 MAPK2/ERK2 89 4 93 1 85 3 89 5 ERK8 21 2 28 1 21 1 19 1 MAPKAP-KIa 90 1 95 4 85 5 92 1 MAPKAP-KJb 80 1 87 4 67 1 95 4 MAPKAP-K2 112 2 111 9 69 1 82 5 MAPKAP-K3 82 2 84 2 88 5 93 1 MSK1 111 1 85_ 259 9 88 3 MNKI 82J 2 69 748 4 52 1 MNK2 77 1 66 9 71 8 98 1 PRAK 93 2 84 1 78 1 75 3 PKA 86 1 89 175 5 92 2 PKCa 81 0 93 6 78 1 101 1 PDKI 95 0 103 2 96 1 95 1 PKBph 98 5 95 5 58 3 107 7 PKBb 96 8 97 3 77 4 101 7 SGK 84 6 112 3 45 8 62 3 CAMK-1 110 1 99 2 60 2 94 8 smMLCK 104 6 97 6 71 2 76 6 EFK2 100 1 90 9 85 1 101 0 S6K 83 3 87 2 69 5 93 9 GSK3b 82 7 91 2 73 5 72 1 ROCK-Il 81 0 64 6 81 1 61 6 PRK2 ____ 83 3 48 2 54 7 45 0 AMPK 83 2 86 4 52 3 103 4 CHK1 67 6 110 7 81 7 86 5 CHK2 89 3 87 5 57 5 79 6 CKI 65 5 73 5 48 2 21 2 CK2 88 1 61 3 12 141 9 PHK 88 8 86 3 63 9 82 2 Lck 87 2 98 4 68 4 91 5 CSK 90 1 107 6 92 1 101 9 Src 65 5 105 3 83 0 98 6 CDK2/cyclin A 98 5 82 4 77 5 62 9 DYRKIa 8 2 ii 1 3 0 1 1 EK2a 109 2 106 0 83 5 111 7 EK6 87 5 94 7 92 1 99 2 NEK7 115 6 96 2 56 9 92 2 IKKb 82 5 76 2 69 5 73 1 PIM2 101 4 78 3 57 0 41 1 SRPKI 97 3 105 5 72 11 83 6 Aurora B 112 1 96 3 83 6 102 1 MARK3 103 6 97 8 84 5 86 1 MST2 105 3 108 2 74 1 81 1 PKD1 101 5 71 4 21 4 53 6 PLK1 100 9 128 4 81 4 87 3
Claims (12)
- Claims I. Use of a compound or salt or hydroxide thereof of thefollowing formula (1) wherein R1 is selected from hydrogen; substituted or unsubstituted C1-C6 alkyl, alkenyl, or alkyloxy, alkylthjo, alkyloxycarbonyl; hydroxyl; nitro; amino; halo or oxo; R2 and R3 are independently selected from hydrogen; substituted or unsubstituted C,-C6 alkyl, alkenyl, or alkyloxy, alkylthio, alkyloxycarbonyl; hydroxyl; nitro; amino or halo; and R4 is selected from hydrogen; substituted or unsubstituted C,-C6 alkyl, alkenyl, or alkyloxycarbonyl; the dashed line represents a single or double bond, for the manufacture of a medicament for alleviating or minimising a symptom or condition observed in a Down's syndrome subject.
- 2. The use of claim 1, wherein the compound is administered to a Down's syndrome subject from birth, or soon thereafter, until adolescence or possibly into and during adulthood.
- 3. The use of any preceding claim, wherein R1, R2 and R3 are independently selected from hydrogen, hydroxyl or C1-C6 alkyl or alkyloxy; and R4 is selected from hydrogen or C1-C6 alkyl.
- 4. The use of any preceding claim, wherein the salts are formed by preparing a quatemary ammonium salt at one or more of the nitrogen atoms.
- 5. The use of any preceding claim, wherein the compounds are selected from the group consisting of: (i) Harmine, where R1 is H, R2 is CH3, R3 is OCH3, R4 is H and the dashed line is a double bond; (ii) Harmaline, where R1 is H, R2 is CH3, R3 is OCR3, R4 is H and the dashed line is a single bond; (iii) Harmane, where R1 is H, R2 is Cl-I3, R3 is H, R4 is H and the dashed line is a double bond; and (iv) Harmalol, where R1 is H, R2 is CH3, R3 is OH, R is H and the dashed line is a single bond.
- 6. A pharmaceutical formulation, comprising a compound or physiologically acceptable salt, hydroxide or other physiologically functional derivative thereof, of the following formula (1) wherein R1 is selected from hydrogen; substituted or unsubstituted Cj-C6 alkyl, alkenyl, or alkyloxy, alkylthio, alkyloxycarbonyl; hydroxyl; nitro; amino; halo or oxo; R2 and R3 are independently selected from hydrogen; substituted or unsubstituted C-C6 alkyl, alkenyl, or alkyloxy, alkylthio, alkyloxycarbonyl; hydroxyl; nitro; amino or halo; and R1 is selected from hydrogen; substituted or unsubstituted C1-C6 alkyl, alkenyl, or alkyloxycarbonyl; the dashed line represents a single or double bond, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic andlor prophylactic ingredients.
- 7. The pharmaceutical formulation of claim 6, wherein R1, R2 and R3 are independently selected from hydrogen, hydroxyl or C1-C6 alkyl or alkyloxy; and R4 is selected from hydrogen or C1-C6 alkyl.
- 8. The pharmaceutical formulation of claims 6 or 7, wherein the salts are formed by preparing a quaternary animonium salt at one or more of the nitrogen atoms.
- 9. The pharmaceutical formulation of claims 6, 7 or 8, wherein the compounds are selected from the group consisting of: (i) Harmine, where R is H, R2 is CH3, R3 is OCH3, R4 is H and the dashed line is a double bond; (ii) Harmaljne, where R1 is H, R2 is CH3, R3 is OCH3, R4 is H and the dashed line is a single bond; (iii) Harrnane, where R1 is H, R2 is CH3, R3 is H, R4 is 1-I and the dashed line is a double bond; and (iv) Harmalol, where R1 is H, R2 is Cl-I3, R3 is OH, R4 is H and the dashed line is a single bond.
- 10. The pharmaceutical formulation of any of claims 6-9, suitable for oral, topical (including dermal, buccal and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular and intravenous), nasal and/or pulmonary administration e.g., by inhalation.
- 11. The pharmaceutical formulation of claim 10, wherein when suitable for pulmonary administration via the buccal cavity, particles containing an active compound have a diameter in the range of 0.5 to 7 microns and are delivered to the bronchial tree of the recipient.
- 12. The use of claim 1-5 or formulation of claim 6-Il, wherein the dosage of the compound is sufficient to alleviate or minimise a symptom or condition observed in a Down's syndrome subject, whilst not eliciting an hallucinogenic effect on the subject.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0705566.8A GB0705566D0 (en) | 2007-03-23 | 2007-03-23 | Method of treating learning impairment in down's syndrome subjects |
Publications (2)
Publication Number | Publication Date |
---|---|
GB0805357D0 GB0805357D0 (en) | 2008-04-30 |
GB2447791A true GB2447791A (en) | 2008-09-24 |
Family
ID=38024674
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GBGB0705566.8A Ceased GB0705566D0 (en) | 2007-03-23 | 2007-03-23 | Method of treating learning impairment in down's syndrome subjects |
GB0805357A Withdrawn GB2447791A (en) | 2007-03-23 | 2008-03-25 | Pharmaceutical formulations and compounds for use in alleviating conditions related to Down's syndrome |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GBGB0705566.8A Ceased GB0705566D0 (en) | 2007-03-23 | 2007-03-23 | Method of treating learning impairment in down's syndrome subjects |
Country Status (1)
Country | Link |
---|---|
GB (2) | GB0705566D0 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011161256A1 (en) * | 2010-06-25 | 2011-12-29 | Facultes Universitaires Notre Dame De La Paix | Beta carboline derivatives useful in the treatment of proliferative disorders |
WO2013026806A1 (en) | 2011-08-19 | 2013-02-28 | Exonhit Sa | Dyrk1 inhibitors and uses thereof |
CN103145705A (en) * | 2012-06-14 | 2013-06-12 | 南通大学 | Beta-carboline alkaloid derivatives and their preparation method and medical use |
EP3768267A4 (en) * | 2018-03-20 | 2022-04-20 | Icahn School of Medicine at Mount Sinai | Kinase inhibitor compounds and compositions and methods of use |
US11547712B2 (en) | 2017-11-20 | 2023-01-10 | Icahn School Of Medicine At Mount Sinai | Kinase inhibitor compounds and compositions and methods of use |
US11788064B2 (en) | 2018-01-05 | 2023-10-17 | Icahn School Of Medicine At Mount Sinai | Method of increasing proliferation of pancreatic beta cells, treatment method, and composition |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110742885B (en) * | 2019-11-04 | 2022-12-20 | 五邑大学 | Application of Harbin in preparation of lipid-lowering drugs |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19807993A1 (en) * | 1998-02-26 | 1999-09-02 | Bayer Ag | Treating tumor necrosis factor mediated inflammatory disease, e.g. arteriosclerosis, using new or known beta-carboline derivatives |
WO2000002878A1 (en) * | 1998-07-11 | 2000-01-20 | University Of Bristol | Compounds having activity at imidazoline receptors |
WO2001068648A1 (en) * | 2000-03-15 | 2001-09-20 | Aventis Pharma Deutschland Gmbh | Substituted beta-carbolines with ikb-kinase inhibiting activity |
WO2005007672A2 (en) * | 2003-06-20 | 2005-01-27 | Coley Pharmaceutical Gmbh | Small molecule toll-like receptor (tlr) antagonists |
FR2869540A1 (en) * | 2004-04-30 | 2005-11-04 | Centre Nat Rech Scient | PHARMACEUTICAL COMPOSITIONS CONTAINING B-CARBOLINE DERIVATIVES AND THEIR USE FOR THE TREATMENT OF CANCER |
-
2007
- 2007-03-23 GB GBGB0705566.8A patent/GB0705566D0/en not_active Ceased
-
2008
- 2008-03-25 GB GB0805357A patent/GB2447791A/en not_active Withdrawn
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19807993A1 (en) * | 1998-02-26 | 1999-09-02 | Bayer Ag | Treating tumor necrosis factor mediated inflammatory disease, e.g. arteriosclerosis, using new or known beta-carboline derivatives |
WO2000002878A1 (en) * | 1998-07-11 | 2000-01-20 | University Of Bristol | Compounds having activity at imidazoline receptors |
WO2001068648A1 (en) * | 2000-03-15 | 2001-09-20 | Aventis Pharma Deutschland Gmbh | Substituted beta-carbolines with ikb-kinase inhibiting activity |
WO2005007672A2 (en) * | 2003-06-20 | 2005-01-27 | Coley Pharmaceutical Gmbh | Small molecule toll-like receptor (tlr) antagonists |
FR2869540A1 (en) * | 2004-04-30 | 2005-11-04 | Centre Nat Rech Scient | PHARMACEUTICAL COMPOSITIONS CONTAINING B-CARBOLINE DERIVATIVES AND THEIR USE FOR THE TREATMENT OF CANCER |
US20080069899A1 (en) * | 2004-04-30 | 2008-03-20 | Jossang Born Yanagida Akino | Pharmaceutical Compositions Comprising Beta-Carboline Derivatives and Use Thereof for the Treatment of Cancer |
Non-Patent Citations (2)
Title |
---|
Behavioural Pharmacology 2004, 15(2), 123-131, Celerier et al. * |
TheScientificWorldJournal 2007, 7, 204-223, Venault et al. * |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013533239A (en) * | 2010-06-25 | 2013-08-22 | ファキュルテ ユニヴェルシテール ノートル−ダム ド ラ ペ | Β-carboline derivatives useful for the treatment of proliferative diseases |
WO2011161256A1 (en) * | 2010-06-25 | 2011-12-29 | Facultes Universitaires Notre Dame De La Paix | Beta carboline derivatives useful in the treatment of proliferative disorders |
US9168247B2 (en) | 2010-06-25 | 2015-10-27 | Facultes Universitaires Notre Dame De La Paix | Beta carboline derivatives useful in the treatment of proliferative disorders |
EA026377B1 (en) * | 2011-08-19 | 2017-04-28 | Диаксонхит | Dyrk1 inhibitors and uses thereof |
KR102006749B1 (en) | 2011-08-19 | 2019-08-02 | 디악쏘니 | Dyrk1 inhibitors and uses thereof |
CN103797002A (en) * | 2011-08-19 | 2014-05-14 | 迪亚克森海特公司 | Dyrk1 inhibitors and uses thereof |
JP2014525928A (en) * | 2011-08-19 | 2014-10-02 | ディアクソンヒット | DYRK1 inhibitors and uses thereof |
KR20140057614A (en) * | 2011-08-19 | 2014-05-13 | 디악쏘니 | Dyrk1 inhibitors and uses thereof |
WO2013026806A1 (en) | 2011-08-19 | 2013-02-28 | Exonhit Sa | Dyrk1 inhibitors and uses thereof |
US9446044B2 (en) | 2011-08-19 | 2016-09-20 | Diaxonhit | DYRK1 inhibitors and uses thereof |
AU2012298510B2 (en) * | 2011-08-19 | 2016-10-27 | Diaxonhit | DYRK1 inhibitors and uses thereof |
CN103797002B (en) * | 2011-08-19 | 2017-02-22 | 迪亚克森海特公司 | Dyrk1 inhibitors and uses thereof |
CN103145705B (en) * | 2012-06-14 | 2016-04-06 | 南通大学 | Beta-carboline alkaloid derivative, its preparation method and medicinal use thereof |
CN103145705A (en) * | 2012-06-14 | 2013-06-12 | 南通大学 | Beta-carboline alkaloid derivatives and their preparation method and medical use |
US11547712B2 (en) | 2017-11-20 | 2023-01-10 | Icahn School Of Medicine At Mount Sinai | Kinase inhibitor compounds and compositions and methods of use |
US11788064B2 (en) | 2018-01-05 | 2023-10-17 | Icahn School Of Medicine At Mount Sinai | Method of increasing proliferation of pancreatic beta cells, treatment method, and composition |
EP3768267A4 (en) * | 2018-03-20 | 2022-04-20 | Icahn School of Medicine at Mount Sinai | Kinase inhibitor compounds and compositions and methods of use |
US11866427B2 (en) | 2018-03-20 | 2024-01-09 | Icahn School Of Medicine At Mount Sinai | Kinase inhibitor compounds and compositions and methods of use |
Also Published As
Publication number | Publication date |
---|---|
GB0805357D0 (en) | 2008-04-30 |
GB0705566D0 (en) | 2007-05-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
GB2447791A (en) | Pharmaceutical formulations and compounds for use in alleviating conditions related to Down's syndrome | |
Świderska et al. | Role of PI3K/AKT pathway in insulin-mediated glucose uptake | |
Fu et al. | Mitochondrial dynamics: biogenesis, fission, fusion, and mitophagy in the regulation of stem cell behaviors | |
Liang et al. | Stem cells, redox signaling, and stem cell aging | |
Madhusoodanan et al. | NO-cGMP signaling and regenerative medicine involving stem cells | |
Nichol et al. | Synthesis of citrovorum factor from folic acid by liver slices; augmentation by ascorbic acid. | |
Pujol et al. | The central metabolism of serotonin in the cat during insomnia. A neurophysiological and biochemical study after administration of p-chlorophenylalanine or destruction of the raphe system | |
Mizukami et al. | Methylcobalamin effects on diabetic neuropathy and nerve protein kinase C in rats | |
US20100063085A1 (en) | Method of treating learning impairment in down's syndrome subjects | |
Krymskaya et al. | PI3K/mTORC1 activation in hamartoma syndromes: therapeutic prospects | |
HU225341B1 (en) | Bis(n-substituted)-staurosporine derivatives, their use and pharmaceutical composition containing thereof | |
JP2013500257A (en) | Treatment of liver damage with PI3K inhibitors | |
FR2753098A1 (en) | PHARMACEUTICAL COMPOSITION COMPRISING AT LEAST ONE NO SYNTHASE INHIBITOR AND AT LEAST ONE TRAP FOR REACTIVE OXYGEN FORMS | |
Downes et al. | Stimulation of PI 3-kinase signaling via inhibition of the tumor suppressor phosphatase, PTEN | |
McAndrew | Fat metabolism and cancer | |
Ikeda et al. | Phorbol ester stimulates acetylcholine synthesis in cultured endothelial cells isolated from porcine cerebral microvessels | |
Majeed et al. | Therapeutic targeting of cancer cell metabolism: role of metabolic enzymes, oncogenes and tumor suppressor genes | |
Mangoura et al. | Programmed cell death in cortical chick embryo astrocytes is associated with activation of protein kinase PK60 and ceramide formation | |
Badwey et al. | Paradoxical effects of retinal in neutrophil stimulation | |
MXPA04007675A (en) | Pharmaceutical composition for regeneration of cirrhotic liver. | |
KR20100065913A (en) | Composition for treating neurodegenerative disease, or alleviating or preventing symptoms thereof by using ecklonia cava extracts | |
US20170065653A1 (en) | Phosphodiesterase Inhibiting Phytochemical Compositions | |
WO2017170981A1 (en) | Prophylactic or therapeutic agent for fgfr3 disease | |
US20210379072A1 (en) | Novel uses | |
McGown et al. | Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |