ES2665461T3 - Moduladores del receptor esfingosina 1-fosfato y métodos de síntesis quiral - Google Patents
Moduladores del receptor esfingosina 1-fosfato y métodos de síntesis quiral Download PDFInfo
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- ES2665461T3 ES2665461T3 ES10830877.6T ES10830877T ES2665461T3 ES 2665461 T3 ES2665461 T3 ES 2665461T3 ES 10830877 T ES10830877 T ES 10830877T ES 2665461 T3 ES2665461 T3 ES 2665461T3
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- alkyl
- independently
- cooh
- coor1
- optionally substituted
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- 229940127530 Sphingosine 1-Phosphate Receptor Modulators Drugs 0.000 title 1
- 238000001308 synthesis method Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 5
- 125000005842 heteroatom Chemical group 0.000 abstract 4
- 229910052757 nitrogen Inorganic materials 0.000 abstract 4
- 125000001963 4 membered heterocyclic group Chemical group 0.000 abstract 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 abstract 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 abstract 2
- 125000005843 halogen group Chemical group 0.000 abstract 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract 2
- 125000002883 imidazolyl group Chemical group 0.000 abstract 2
- 125000002757 morpholinyl group Chemical group 0.000 abstract 2
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 2
- 125000003386 piperidinyl group Chemical group 0.000 abstract 2
- 125000003226 pyrazolyl group Chemical group 0.000 abstract 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 abstract 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 125000002393 azetidinyl group Chemical group 0.000 abstract 1
- -1 benzoimidazolyl Chemical group 0.000 abstract 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract 1
- 125000004193 piperazinyl group Chemical group 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 239000012453 solvate Substances 0.000 abstract 1
- 125000001424 substituent group Chemical group 0.000 abstract 1
- 125000000335 thiazolyl group Chemical group 0.000 abstract 1
- 102100025750 Sphingosine 1-phosphate receptor 1 Human genes 0.000 description 13
- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 description 10
- 101710155454 Sphingosine 1-phosphate receptor 1 Proteins 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- SUZLHDUTVMZSEV-UHFFFAOYSA-N Deoxycoleonol Natural products C12C(=O)CC(C)(C=C)OC2(C)C(OC(=O)C)C(O)C2C1(C)C(O)CCC2(C)C SUZLHDUTVMZSEV-UHFFFAOYSA-N 0.000 description 5
- OHCQJHSOBUTRHG-UHFFFAOYSA-N colforsin Natural products OC12C(=O)CC(C)(C=C)OC1(C)C(OC(=O)C)C(O)C1C2(C)C(O)CCC1(C)C OHCQJHSOBUTRHG-UHFFFAOYSA-N 0.000 description 5
- 101000693265 Homo sapiens Sphingosine 1-phosphate receptor 1 Proteins 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- ZZMYWYZPNZRYPX-SANMLTNESA-N (2r)-2-amino-2-[5-[4-[2-(4-phenylphenyl)ethoxy]-3-(trifluoromethyl)phenyl]-1h-imidazol-2-yl]propan-1-ol Chemical compound N1C([C@@](N)(CO)C)=NC=C1C(C=C1C(F)(F)F)=CC=C1OCCC1=CC=C(C=2C=CC=CC=2)C=C1 ZZMYWYZPNZRYPX-SANMLTNESA-N 0.000 description 2
- 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 2
- 102100029802 Sphingosine 1-phosphate receptor 5 Human genes 0.000 description 2
- 101710155451 Sphingosine 1-phosphate receptor 5 Proteins 0.000 description 2
- 108050001083 Sphingosine 1-phosphate receptors Proteins 0.000 description 2
- 102000011011 Sphingosine 1-phosphate receptors Human genes 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000005400 testing for adjacent nuclei with gyration operator Methods 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101001021281 Homo sapiens Protein HEXIM1 Proteins 0.000 description 1
- 102100025749 Sphingosine 1-phosphate receptor 2 Human genes 0.000 description 1
- 101710155462 Sphingosine 1-phosphate receptor 2 Proteins 0.000 description 1
- 102100029803 Sphingosine 1-phosphate receptor 4 Human genes 0.000 description 1
- 101710155458 Sphingosine 1-phosphate receptor 4 Proteins 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory 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
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- 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
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Virology (AREA)
- Immunology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Oncology (AREA)
- Rheumatology (AREA)
- Transplantation (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Psychiatry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Un compuesto que tiene la estructura de las Fórmulas I-R o I-S o una sal, un hidrato o un solvato farmacéuticamente aceptables del mismo: **(Ver fórmula)** en las que X es -NR'R" o -OR'''; Y es -CN, -Cl, -CF3, I, -COOH o -COOR1; R' es H, alquilo C1-4, n-hidroxialquilo C1-4, -SO2-R1 o -CO-R1; R" es H, -SO2-R3, alquilo C1-4 opcionalmente sustituido con 1 o más R2, o un resto de anillo opcionalmente sustituido con R4 en donde dicho resto de anillo es piperidinilo, ciclohexilo, morfolinilo, tiazolilo, pirazolilo, pirrolidinilo, imidazolilo o fenilo; o R' y R" tomados junto con el átomo de nitrógeno al que están unidos forman un anillo heterocíclico saturado de 4, 5 o 6 miembros que contiene 0 o 1 heteroátomos adicionales donde dicho heteroátomo adicional es O o N en donde dicho heterociclo está opcionalmente sustituido de forma individual o múltiple con sustituyentes seleccionados independientemente entre el grupo que consiste en -OH, oxo, -NH2, n-hidroxialquilo C1-4, - COOH, -(CH2)m-COOH, -(CH2)m-COOR1, -N(R1R1) y -(CH2)m-CO-N(R5R5); R"' es H, alquilo C1-4 o -CO-R1; cada R1 es independientemente alquilo C1-4 o H; cada R2 es independientemente H, halo, OH, oxo, >=NH, NH2, -COOH, F, -NHR1, -N(R5R5),-SO2-R1, -SO2- N(R5R5), -N(R1)-SO2-R1, -COOR1, -OCO-R1, -CO-N(R5R5), -N(R1)-COR1, alquilo C1-3, alcoxi C1-3 y un resto de anillo opcionalmente sustituido con R4 en donde dicho resto de anillo es piperazinilo, piperidinilo, morfolinilo, pirrolidinilo, pirazolilo, imidazolilo, benzoimidazolilo, azetidinilo, ciclobutinilo o fenilo; cada R3 es independientemente R2, alquilo C1-4, cicloalquilo C3-6 o alquilo C1-4 opcionalmente sustituido con 1 o más R2; cada R4 es independientemente halo, OH, -NH2, -NHR1, -N(R1R1), -COOH, -COOR1, -NHCO-R1; cada R5 es independientemente alquilo C1-4 o H, o dos R5 tomados junto con el átomo de nitrógeno al que están unidos forman un anillo heterocíclico saturado de 4, 5 o 6 miembros que contiene 0 o 1 heteroátomos adicionales donde dicho heteroátomo adicional es O o N en donde dicho heterociclo está opcionalmente sustituido con -OH, -NH2, -N(R1R1), n-hidroxialquilo C1-4, -(CH2)m-COOH, -(CH2)m-COOR1; y cada m es independientemente 0, 1, 2 o 3.
Description
TABLA 1
- ESTRUCTURA
- NÚMERO DE COMPUESTO TIEMPO DE RETENCIÓN LCMS (min)
- imagen69
- 1 9,32
- imagen70
- 2 9,32
- imagen71
- 3 6,35
- imagen72
- 4 6,34
- imagen73
- 5 9,21
- imagen74
- 6 9,20
70 71 72 73 74 75 76 77 78 79 80 81
- imagen75
- 7 8,09
- imagen76
- 8 8,08
- imagen77
- 9 8,25
- imagen78
- 10 8,26
- imagen79
- 11 9,53
- imagen80
- 12 9,53
- imagen81
- 13 8,16
- imagen82
- 14 8,16
- imagen83
- 15 9,01
- imagen84
- 16 9,03
- imagen85
- 17 8,55
- imagen86
- 18 8,56
- imagen87
- 19 8,31
- imagen88
- 20 6,45
- imagen89
- 21 8,90
- imagen90
- 22 8,89
- imagen91
- 23 9,37
- imagen92
- 24 9,36
- imagen93
- 25 6,56
- imagen94
- 26 8,82
- imagen95
- 27 8,8
- imagen96
- 28 9,41
- imagen97
- 29 9,36
- imagen98
- 30 9,87
- imagen99
- 31 9,83
- imagen100
- 32 9,68
- imagen101
- 33 9,66
- imagen102
- 34 8,83
- imagen103
- 35 8,84
- imagen104
- 36 8,73
- imagen105
- 37 8,76
- imagen106
- 38 8,47
- imagen107
- 39 8,49
- imagen108
- 40 9,09
- imagen109
- 41 9,07
- imagen110
- 42 9,00
- imagen111
- 43 9,02
- imagen112
- 44 6,74
- imagen113
- 45 6,82
- imagen114
- 46 6,69
- imagen115
- 47 6,58
- imagen116
- 48 6,55
- imagen117
- 49 6,54
- imagen118
- 50 6,36
- imagen119
- 51 6,40
- imagen120
- 52 6,13
- imagen121
- 53 6,52
- imagen122
- 54 6,71
- imagen123
- 55 6,76
- imagen124
- 56 8,63
- imagen125
- 57 6,16
- imagen126
- 58 6,34
- imagen127
- 59 5,85
- imagen128
- 60 8,56
- imagen129
- 61 6,07
- imagen130
- 62 6,22
- imagen131
- 63 6,33
- imagen132
- 64 6,43
- imagen133
- 65 6,00
- imagen134
- 66 6,23
- imagen135
- 67 7,40
- imagen136
- 68 9,66
- imagen137
- 69 10,74
- imagen138
- 70 8,81
- imagen139
- 71 7,44
Ensayos biológicos
5
Generación de la inhibición mediada por S1P1 del ensayo indicador de AMPc
Un plásmido de expresión en mamífero que contiene S1P1/EDG1 clonado pcDNA3.1 se adquirió del Missouri S&T cDNA Resource Centre. La secuencia de nucleótidos y de aminoácidos del S1P1/EDG1 humano se ha publicado en 10 Hla y Maciag (J Biol Chem, 265(1990), 9308-9313). S1P1/pcDNA3.1 se transfectó en la línea de células CRE-bla CHO K1 (Invitrogen), y los clones monocelulares estables se seleccionaron usando técnicas convencionales. La expresión del receptor S1P1/EDG1 funcional se confirmó mediante FACS de la superficie celular con un anticuerpo dirigido contra S1P1 (R&D Systems, clone 218713) y la inhibición de AMPc inducida por forskolina mediada por S1P.
15 Ensayo indicador de S1P1 CRE-bla CHOK1 -caracterización de agonistas de S1P1
Las células se sembraron en placas de 384 pocillos de paredes negras y fondo transparente a 104 células/pocillo/19,5 µl de medio de ensayo exento de eDMEM-fenol, carbón activo al 0,5 %/suero desprovisto de dextrano, glutamina 2 mM, NEAA 0,1 mM, Na-Piruvato 1 mM, Hepes 25 mM) y se incubaron durante 18 h a 37°C en 20 CO2 al 5 %. Se generaron curvas de respuesta a la dosis (10 puntos) en HEPES 10 mM, Pluronic F127 al 0,1 %, en presencia de forskolina. Las células se trataron con 0,5 µl de compuesto en presencia de forskolina 2 µM durante 4 h a 37°C. El sustrato fluorescente de β-lactamasa basado en FRET (LiveBLAzer™-FRET B/G Loading Kit CC4-AM; Invitrogen) se preparó de acuerdo con las directrices del fabricante, y se incubó con las células durante 2 horas a
82
temperatura ambiente. Las placas se leyeron a Ex:410/Em:458 y Ex:410/Em:522, y se determinó la relación de respuesta. Los datos se analizaron mediante regresión no lineal para determinar la CE50 para la inhibición de AMPc inducido por forskolina.
5 Especificidad respecto de otros receptores S1P
Para evaluar la especificidad del compuesto sobre otros receptores S1P, se usaron las siguientes líneas celulares: S1P2 CRE-bla CHOK1, S1P3-Gα15 NFAT-bla HEK293T (Invitrogen), S1P4-bla TANGO U2OS (Invitrogen), S1P5-bla TANGO U2OS (Invitrogen). Se usó el mismo ensayo configurado para S1P1 pero sin forskolina. Los ensayos con
10 S1P4 y S1P5 se realizaron en medio FreeStyle Expression (Invitrogen). Las células S1P5 se incubaron durante 48 h antes del tratamiento con el compuesto.
Actividad de S1P1 indicada
15 Los datos de actividad de agonistas de S1P1 seleccionados se muestra en la Tabla 2. El intervalo de actividad se denota de la siguiente forma: ++++ representa actividad agonista <0,05 nM. +++ representa actividad agonista entre 0,05 y 0,50 nM, y ++ representa actividad agonista entre 0,50-5,00 nM, y + representa actividad agonista > 5,00 nM. N/A representa no disponible.
20 TABLA 2
- NÚMERO DE COMPUESTO
- ACTIVIDAD S1P1 NÚMERO DE COMPUESTO ACTIVIDAD S1P1
- 1
- +++ 36 ++++
- 2
- ++++ 37 ++++
- 3
- ++ 38 ++++
- 4
- +++ 39 ++++
- 5
- +++ 40 ++++
- 6
- +++ 41 ++++
- 7
- +++ 42 ++++
- 8
- +++ 43 ++++
- 9
- +++ 44 +++
- 10
- +++ 45 ++
- 11
- +++ 46 ++
- 12
- +++ 47 +++
- 13
- +++ 48 +++
- 14
- +++ 49 +++
- 15
- +++ 50 +++
- 16
- ++ 51 +++
- 17
- ++ 52 ++++
- 18
- ++ 53 +++
- 19
- ++ 54 ++
- 20
- ++ 55 +++
- 21
- +++ 56 ++
- 22
- +++ 57 ++
- 23
- ++ 58 +
- 24
- +++ 59 +
- 25
- ++ 60 +
- 26
- +++ 61 +
83
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imagen1 imagen2 imagen3 imagen4 imagen5 imagen6 imagen7 imagen8 imagen9 imagen10
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