WO2006065218A1 - Novel molecular probes - Google Patents
Novel molecular probes Download PDFInfo
- Publication number
- WO2006065218A1 WO2006065218A1 PCT/SE2005/001920 SE2005001920W WO2006065218A1 WO 2006065218 A1 WO2006065218 A1 WO 2006065218A1 SE 2005001920 W SE2005001920 W SE 2005001920W WO 2006065218 A1 WO2006065218 A1 WO 2006065218A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- oxo
- mmol
- oxa
- aza
- Prior art date
Links
- 239000003068 molecular probe Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 65
- -1 3-benzoylphenyl Chemical group 0.000 claims description 22
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 20
- 125000002140 imidazol-4-yl group Chemical group [H]N1C([H])=NC([*])=C1[H] 0.000 claims description 11
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 10
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims 4
- 238000002955 isolation Methods 0.000 abstract description 11
- 102000004190 Enzymes Human genes 0.000 abstract description 4
- 108090000790 Enzymes Proteins 0.000 abstract description 4
- 238000012512 characterization method Methods 0.000 abstract description 2
- 238000001514 detection method Methods 0.000 abstract description 2
- 230000004807 localization Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 59
- 238000005160 1H NMR spectroscopy Methods 0.000 description 55
- 238000000034 method Methods 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
- 239000000203 mixture Substances 0.000 description 34
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
- 239000007787 solid Substances 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
- 101150041968 CDC13 gene Proteins 0.000 description 24
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 238000000746 purification Methods 0.000 description 22
- 239000007858 starting material Substances 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 239000002253 acid Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000377 silicon dioxide Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 239000007832 Na2SO4 Substances 0.000 description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 11
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 11
- 150000001412 amines Chemical class 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 0 C*C(N*NC(CN(c(cccc1)c1O[C@]([C@@]1NC([C@](C)NC(Cc2cc(C(c3ccccc3)=O)ccc2)=O)=O)c2ccccc2)C1=O)=O)=O Chemical compound C*C(N*NC(CN(c(cccc1)c1O[C@]([C@@]1NC([C@](C)NC(Cc2cc(C(c3ccccc3)=O)ccc2)=O)=O)c2ccccc2)C1=O)=O)=O 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
- 208000024827 Alzheimer disease Diseases 0.000 description 7
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 6
- ASCHNMXUWBEZDM-UHFFFAOYSA-N chloridodioxygen(.) Chemical compound [O]OCl ASCHNMXUWBEZDM-UHFFFAOYSA-N 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
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- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 5
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- VHRGRCVQAFMJIZ-UHFFFAOYSA-N cadaverine Chemical compound NCCCCCN VHRGRCVQAFMJIZ-UHFFFAOYSA-N 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 4
- YYPNFMVXEYTUBA-VQTJNVASSA-N (2R,3S)-3-amino-7-(5-aminopentoxy)-5-methyl-2-phenyl-2,3-dihydro-1,5-benzoxazepin-4-one Chemical compound CN(C(C=C(C=C1)OCCCCCN)=C1O[C@@H]([C@@H]1N)C2=CC=CC=C2)C1=O YYPNFMVXEYTUBA-VQTJNVASSA-N 0.000 description 4
- UCVSHLAPFBZRQT-LSDHHAIUSA-N (2r,3s)-n-(2-hydroxy-5-methoxyphenyl)-3-phenyloxirane-2-carboxamide Chemical compound COC1=CC=C(O)C(NC(=O)[C@H]2[C@@H](O2)C=2C=CC=CC=2)=C1 UCVSHLAPFBZRQT-LSDHHAIUSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
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- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
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- CPGVZYCGBPJWDZ-FASAQXTFSA-N methyl 2-[(2r,3s)-3-[[(2s)-2-aminopropanoyl]amino]-4-oxo-2-phenyl-2,3-dihydro-1,5-benzoxazepin-5-yl]acetate Chemical compound C1([C@H]2OC3=CC=CC=C3N(C([C@H]2NC(=O)[C@H](C)N)=O)CC(=O)OC)=CC=CC=C1 CPGVZYCGBPJWDZ-FASAQXTFSA-N 0.000 description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
Definitions
- the present invention relates to novel molecular probes useful for the detection, characterization, localization and isolation of the ⁇ -secretase enzyme.
- AD Alzheimer's Disease
- AD is a progressive, neurodegenerative disease characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability.
- AD is a common cause of dementia in humans and a leading cause of death in the United States.
- AD has been observed in races and ethnic groups worldwide and presents a major public health problem throughout the world. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available and the disease is currently considered among experts to be incurable.
- the histopathological manifestations of AD are characteristic lesions known as amyloid (or senile) plaques and neurofibrillar tangles that are found in the regions of the brain associated with memory, reasoning and cognition.
- Amyloid ⁇ protein is derived from the proteolytic cleavage of amyloid precursor protein (APP). Processing of APP to amyloid ⁇ protein and other APP fragments is governed by a group of enzymes known as secretases.
- secretases One type of secretase, ⁇ -secretase, is responsible for the protein cleavage that produces amyloid ⁇ protein.
- PSl presenilin 1
- R 1 is selected from m-benzoyl, p-benzoyl, or p-azido;
- R 2 is independently selected from H, -CH 3 ,
- R is independently selected from H or
- N 1 [(2R,3R)-5-(2-oxo-2- ⁇ [5-( ⁇ 4-[(3a5,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-rf]imidazol- 4-yl]butanoyl ⁇ amino)pentyl]amino ⁇ ethyl)-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin- 3-yl]-N 2 -[(4-triaza-1,2-dien-2-ium-1-ylphenyl)acetyl]-L-alaninamide;
- N 1 N 1 -[(25,35)-5-(2-oxo-2- ⁇ [5-( ⁇ 4-[(3a l S',4S,6aR)-2-oxohexahydro-1i7-thieno[3,4-cr
- any variable e.g., R 1 , R 7 , R a , R e etc.
- its definition at each occurrence is independent of its definition at every other occurrence.
- R 1 e.g., R 1 , R 7 , R a , R e etc.
- the compounds herein described may have asymmetric centers.
- the compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis.
- the compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Such methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety by reference.
- the novel compounds of this invention may be prepared using the reactions and techniques described in this application. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected.
- NMM denotes N-methylmorpholine p-TSA p-toluenesulfonic acid
- Preparative Reverse Phase Liquid Chromatography-Research samples were purified* using a Gilson preparative chromatography system. Samples were purified using either a Hewlett Packard CombiHT SB-Cl 8 semi-preparative column (5 ⁇ m, 21.2 mm x 150 mm; part# 870150-902 KJ1018) or a Modcol C18 preparative column (10 ⁇ m, 50.8 mm x 250 mm; part# PA000-050025). Flow rates; semi-preparative column (20 mL/min), preparative column (50-80 mL/min). Eluent consisted of a mixture of MeCN/H 2 O modified w/0.1 % TFA.
- a typical sequence consisted of: a) An equilibration (for 3 min at starting gradient concentration) b) A gradient (started at 40-50% MeCN and ran to 90% MeCN over 7-15 minutes) c) A flush (for 5 min at 90% MeCN)
- Example 1 5-((3aR,6S,6aS)-2-Oxo-hexahvdro-thienof3,4- ⁇ /limidazol-6-yl)-pentanoic acid ⁇ 5-f2-((6R.7SV7- ⁇ (SV2-12-(3-benzovl-phenvlVacetylamino1-propionvlamino ⁇ -8- oxo- ⁇ -phenyl-V ⁇ -dihvdro- ⁇ fir-S-oxa ⁇ -aza-benzocvclohepten-g-ylVacetylaminol- pentvU-amide (1)
- Example 2 S-f ⁇ aR ⁇ S ⁇ ⁇ aS ⁇ -Oxo ⁇ iexahvdro-thienoP ⁇ -./limidazoI- ⁇ -ylVpentanoic acid (5-f2-((6R,7S)-7-((S)-2-f2-(4-benzoyl-phenylVacetylam ⁇ no1-propionvIaminol-8- oxo-6-phenyl-7.,8-dihvdro-6fl-5-oxa-9-aza-benzocvclohepten-9-yl)-acetylaminol- pentvU-amide (2)
- Example 3 5-f (3aR,6S,6aS)-2-Oxo-hexahvdro-thieno [3,4- ⁇ flimidazol-6-yl)-pentanoic acid ⁇ 5-f2-((6R,7S)-7- ⁇ (S)-2-f2-(4-azido-phenvI)-acetvIammol-propionyIamino ⁇ -8-oxo- 6-phenyl-7,8-dihydro-6fl-5-oxa-9-aza-benzocvclohepten-9-ylVacetylamino1-pentvU- amide (3)
- Example 4 5-((3aR,6S,6aS)-2-Oxo-hexahvdro-thieno[3,4- ⁇ imidazol-6-yl)-pentanoic acid ⁇ 5-r2-((6S,7R)-7- ⁇ (S)-2-f2-(3-benzovI-phenvI)-acetylaminol-propionylamino>-8- oxo-6-phenyl-7,8-dihvdro-6g-5-oxa-9-aza-benzocvclohepten-9-ylVacetylamino1- pentyll-amide (4)
- Trifluoromethanesulfonyl chloride (4.5 rnL, 42 mmol) was added via syringe to a stirred solution of (6S,7S)-7-hydroxy-6-phenyl-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8- one (4b) (2.66 g, 10.4 mmol) and Et 3 N (5.8 mL, 42 mmol) in DCM (27 mL) under nitrogen at -18 0 C. The mixture was kept at -18 0 C overnight.
- Aqueous IN HCl was added (15 mL), flask was placed on the Parr® shaker, and evacuated/backfilled with hydrogen (4 cycles). Mixture was shaken under 50 psi hydrogen for 2 h (room temperature was 3 °C), filtered through celite, and EtOH was evaporated. Residue was stirred with 250 mL Et 2 O for 2 h and preciptated product was filtered, washed (Et 2 O), and dried under high vaccum for 18 h. This gave 1.05 g (84%) of a white powder.
- Example 6 5-((3aR,6S,6aS)-2-Oxo-hexahvdro-thienor3.,4- ⁇ limidazol-6-yl)-pentanoic acid ⁇ 5-f2-((6S,7R)-7- ⁇ (S)-2-[2-(4-azido-phenyl)-acetylaminol-propionylamino)-8-oxo- ⁇ -phenyl-T ⁇ -dihydro-fifl-S-oxa-g-aza-benzocvclohepten-P-vD-acetvIaminoi-pentyl ⁇ - amide (6)
- Example 7 5-f(3aR,6S.6aS)-2-Oxo-hexahvdro-thieno[3,4-(/]imidazol-6-ylVpentanoic acid [5-((6R.,7SV7- ⁇ (S)-2-f2-(3-benzovI-phenyl)-acetylaminol-propionylamino ⁇ -9- methyl-8-oxo-6-phenyl-6,7,8.,9-tetrahvdro-5-oxa-9-aza-benzocvclohepten-2-yloxyV pentyli-amide (7) To a solution of 5-((3aR,6S,6aS)-2-oxo-hexahydro-thieno[3,4-cTlimidazol-6-yl)-pentanoic acid ⁇ 5-[(6R,7S)-7-((S)-2-amino- ⁇ ropiony
- Example 8 S-CQaR ⁇ S ⁇ aSVl-Oxo-hexahydro-thienofS ⁇ -f/iimidazol- ⁇ -vD-pentanoic acid f5-((6R,7S)-7- ⁇ (S)-2-r2-(4-benzoy ⁇ -phenyl)-acetylamino1-propionvIamino ⁇ -9- methyl-S-oxo- ⁇ -phenyl- ⁇ ⁇ V ⁇ S ⁇ -tetrahvdro-S-oxa-g-aza-benzocvclohepten-Z-yloxy)- pentyll-amide (8)
- the gamma secretase enzyme assay measures the amount of amyloid ⁇ (A ⁇ )40 product generated by the cleavage of Cl 00, a truncated form of amyloid precursor protein (APP).
- the ClOO substrate is a recombinant protein purified from E. coli inclusion bodies.
- the ⁇ secretase enzyme complex is prepared by detergent extraction of HeLa 8A8 cell membranes. The enzyme reaction contains 10 ul of inhibitor at a defined concentration, diluted from a DMSO stock into 96-well microplates (final concentration of DMSO is maintained at 5%).
- reaction buffer 50 mM MES, pH 6.5, containing 100 mM NaCl, 1 mM EDTA, 1 mM DTT, 1 mg/mL BSA, 0.25% Chapso, 0.01% PE, 0.01% PC and a protease cocktail
- the reactions are initiated by addition of lOul enzyme at a 20-fold dilution from stock.
- An A ⁇ 40 standard curve diluted in the reaction buffer plus ClOO is included in each assay. Plates are incubated for 3 hours at 37 degrees.
- Example 13 Gamma Secretase Whole Cell Assay (GSWC) Preparation of cells for assay: human embryonic kidney (hek) cells stably expressing human amyloid precursor protein (app) and presenelin i were grown in dmem media (fisher mtlOO13cv) containing 10% fetal calf serum (fisher #mtl35011cv), 0.2 mg/ml g418 (fisher #mt30234cr) and Ix concentration of antibiotic/antimycotic mixture (fisher #mt30004ci). cells were grown in tissue culture flasks and passaged every week at a ratio of 1 :30.
- GSWC Gamma Secretase Whole Cell Assay
- Test compounds were solubilized in DMSO at a concentration of 3.3 mM. From this stock solution a dilution series was prepared in complete growth medium of cells. Dilution series were then transferred to 96 well assay plate (Costar #3595) with 100 uL in each well. Cells (100 uL) were added to each well containing test compound. Two controls, one containing only cells (Total) and one containing only growth medium (Background) were also included. Cells were incubated with compounds for 14-16 hours in cell culture incubator.
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WO2000019210A2 (en) * | 1998-09-30 | 2000-04-06 | Elan Pharmaceuticals, Inc. | Determining the mechanism of beta-amyloid peptide generation |
WO2001072324A1 (en) * | 2000-03-28 | 2001-10-04 | Bristol-Myers Squibb Pharma Company | Lactams as inhibitors of a-beta protein production |
WO2004031154A1 (en) * | 2002-10-03 | 2004-04-15 | Astrazeneca Ab | Novel lactams and uses thereof |
WO2004100958A1 (en) * | 2003-05-19 | 2004-11-25 | F. Hoffmann-La Roche Ag | 2, 3, 4, 5-tetrahydrobenzo[f][1, 4]oxazepine-5-carboxylic acid amide derivatives as gamma-secretase inhibitors for the treatment of alzheimer’s disease |
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EP1636196A1 (en) * | 2003-03-14 | 2006-03-22 | AstraZeneca AB | Novel lactams and uses thereof |
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WO2000019210A2 (en) * | 1998-09-30 | 2000-04-06 | Elan Pharmaceuticals, Inc. | Determining the mechanism of beta-amyloid peptide generation |
WO2001072324A1 (en) * | 2000-03-28 | 2001-10-04 | Bristol-Myers Squibb Pharma Company | Lactams as inhibitors of a-beta protein production |
WO2004031154A1 (en) * | 2002-10-03 | 2004-04-15 | Astrazeneca Ab | Novel lactams and uses thereof |
WO2004100958A1 (en) * | 2003-05-19 | 2004-11-25 | F. Hoffmann-La Roche Ag | 2, 3, 4, 5-tetrahydrobenzo[f][1, 4]oxazepine-5-carboxylic acid amide derivatives as gamma-secretase inhibitors for the treatment of alzheimer’s disease |
Non-Patent Citations (2)
Title |
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LI Y.-M. ET AL: "Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1", NATURE, vol. 405, 8 June 2000 (2000-06-08), pages 689 - 694, XP001026218 * |
WOLFE M.S.: "Gamma-Secretase as a Target for Alzheimer's Disease", CURRENT TOPIES IN MEDICINAL CHEMISTRY, vol. 2, 2002, pages 371 - 383, XP002998705 * |
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WO2007104933A1 (en) * | 2006-03-10 | 2007-09-20 | Astrazeneca Ab | Chemical compounds |
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