CN1301131A - 二肽型编程性细胞死亡抑制剂及其用途 - Google Patents
二肽型编程性细胞死亡抑制剂及其用途 Download PDFInfo
- Publication number
- CN1301131A CN1301131A CN98810022A CN98810022A CN1301131A CN 1301131 A CN1301131 A CN 1301131A CN 98810022 A CN98810022 A CN 98810022A CN 98810022 A CN98810022 A CN 98810022A CN 1301131 A CN1301131 A CN 1301131A
- Authority
- CN
- China
- Prior art keywords
- asp
- compound
- ome
- cell death
- cbz
- 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.)
- Granted
Links
- 108010016626 Dipeptides Proteins 0.000 title abstract description 8
- 229940088872 Apoptosis inhibitor Drugs 0.000 title 1
- 239000000158 apoptosis inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 100
- 230000030833 cell death Effects 0.000 claims abstract description 63
- 210000000056 organ Anatomy 0.000 claims abstract description 16
- 210000004027 cell Anatomy 0.000 claims description 103
- 238000000034 method Methods 0.000 claims description 60
- 230000000694 effects Effects 0.000 claims description 33
- 238000011282 treatment Methods 0.000 claims description 29
- 241001465754 Metazoa Species 0.000 claims description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 21
- 230000000302 ischemic effect Effects 0.000 claims description 21
- 210000001519 tissue Anatomy 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 14
- 230000002265 prevention Effects 0.000 claims description 13
- 108090000623 proteins and genes Proteins 0.000 claims description 12
- 230000005855 radiation Effects 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 9
- 210000003491 skin Anatomy 0.000 claims description 9
- 239000002609 medium Substances 0.000 claims description 8
- 239000000651 prodrug Substances 0.000 claims description 8
- 229940002612 prodrug Drugs 0.000 claims description 8
- 201000004384 Alopecia Diseases 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 230000034994 death Effects 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 206010061216 Infarction Diseases 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 6
- 150000001576 beta-amino acids Chemical class 0.000 claims description 6
- 230000007574 infarction Effects 0.000 claims description 6
- 239000002674 ointment Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 208000030507 AIDS Diseases 0.000 claims description 4
- 206010003694 Atrophy Diseases 0.000 claims description 4
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 4
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 claims description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims description 4
- 208000028990 Skin injury Diseases 0.000 claims description 4
- 230000037444 atrophy Effects 0.000 claims description 4
- 210000002569 neuron Anatomy 0.000 claims description 4
- 210000001428 peripheral nervous system Anatomy 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- 238000003860 storage Methods 0.000 claims description 4
- 230000009385 viral infection Effects 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 208000036075 Autosomal dominant tubulointerstitial kidney disease Diseases 0.000 claims description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 206010056370 Congestive cardiomyopathy Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 claims description 3
- 102100034256 Mucin-1 Human genes 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 3
- 230000006378 damage Effects 0.000 claims description 3
- 201000011304 dilated cardiomyopathy 1A Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 210000004209 hair Anatomy 0.000 claims description 3
- 230000006872 improvement Effects 0.000 claims description 3
- 201000006417 multiple sclerosis Diseases 0.000 claims description 3
- 230000004770 neurodegeneration Effects 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 3
- 210000001116 retinal neuron Anatomy 0.000 claims description 3
- 208000002491 severe combined immunodeficiency Diseases 0.000 claims description 3
- 230000035882 stress Effects 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 210000005253 yeast cell Anatomy 0.000 claims description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 2
- 206010010099 Combined immunodeficiency Diseases 0.000 claims description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 2
- 208000024777 Prion disease Diseases 0.000 claims description 2
- 208000007014 Retinitis pigmentosa Diseases 0.000 claims description 2
- 206010068168 androgenetic alopecia Diseases 0.000 claims description 2
- 208000007502 anemia Diseases 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims description 2
- 238000002512 chemotherapy Methods 0.000 claims description 2
- 230000002996 emotional effect Effects 0.000 claims description 2
- 210000003780 hair follicle Anatomy 0.000 claims description 2
- 230000003676 hair loss Effects 0.000 claims description 2
- 210000002216 heart Anatomy 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 210000002865 immune cell Anatomy 0.000 claims description 2
- 208000033065 inborn errors of immunity Diseases 0.000 claims description 2
- 230000004410 intraocular pressure Effects 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- 210000004165 myocardium Anatomy 0.000 claims description 2
- 208000028529 primary immunodeficiency disease Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 230000000630 rising effect Effects 0.000 claims description 2
- 210000000987 immune system Anatomy 0.000 claims 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims 1
- JHKXZYLNVJRAAJ-WDSKDSINSA-N Met-Ala Chemical compound CSCC[C@H](N)C(=O)N[C@@H](C)C(O)=O JHKXZYLNVJRAAJ-WDSKDSINSA-N 0.000 claims 1
- 230000000747 cardiac effect Effects 0.000 claims 1
- 239000006143 cell culture medium Substances 0.000 claims 1
- 230000000913 erythropoietic effect Effects 0.000 claims 1
- 208000024963 hair loss Diseases 0.000 claims 1
- 229960003444 immunosuppressant agent Drugs 0.000 claims 1
- 230000001861 immunosuppressant effect Effects 0.000 claims 1
- 239000003018 immunosuppressive agent Substances 0.000 claims 1
- 230000003387 muscular Effects 0.000 claims 1
- 230000000472 traumatic effect Effects 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 58
- 230000003389 potentiating effect Effects 0.000 abstract description 11
- 230000006907 apoptotic process Effects 0.000 abstract description 7
- 238000003782 apoptosis assay Methods 0.000 description 58
- 230000005522 programmed cell death Effects 0.000 description 47
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 40
- 239000000203 mixture Substances 0.000 description 37
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 33
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 31
- 239000000243 solution Substances 0.000 description 30
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 29
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 28
- 238000005336 cracking Methods 0.000 description 27
- 238000012360 testing method Methods 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 17
- 239000007787 solid Substances 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 102000011727 Caspases Human genes 0.000 description 14
- 108010076667 Caspases Proteins 0.000 description 14
- 238000002474 experimental method Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 102100029855 Caspase-3 Human genes 0.000 description 11
- 108090000397 Caspase 3 Proteins 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 239000003814 drug Substances 0.000 description 9
- 210000004185 liver Anatomy 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 239000000758 substrate Substances 0.000 description 8
- 102000004091 Caspase-8 Human genes 0.000 description 7
- 108090000538 Caspase-8 Proteins 0.000 description 7
- 102000003777 Interleukin-1 beta Human genes 0.000 description 7
- 108090000193 Interleukin-1 beta Proteins 0.000 description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- -1 2,6-dichloro-benzoyl oxygen Chemical compound 0.000 description 6
- 229940123169 Caspase inhibitor Drugs 0.000 description 6
- BQRGNLJZBFXNCZ-UHFFFAOYSA-N calcein am Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(C)=O)=C(OC(C)=O)C=C1OC1=C2C=C(CN(CC(=O)OCOC(C)=O)CC(=O)OCOC(=O)C)C(OC(C)=O)=C1 BQRGNLJZBFXNCZ-UHFFFAOYSA-N 0.000 description 6
- 230000004224 protection Effects 0.000 description 6
- 238000011552 rat model Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 102000035195 Peptidases Human genes 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 5
- 239000004365 Protease Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 231100000225 lethality Toxicity 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 235000019419 proteases Nutrition 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 206010002091 Anaesthesia Diseases 0.000 description 4
- 101000828805 Cowpox virus (strain Brighton Red) Serine proteinase inhibitor 2 Proteins 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 102000000589 Interleukin-1 Human genes 0.000 description 4
- 108010002352 Interleukin-1 Proteins 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 231100000360 alopecia Toxicity 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000010523 cascade reaction Methods 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 239000000975 dye Substances 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 230000003779 hair growth Effects 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 230000004112 neuroprotection Effects 0.000 description 4
- 239000012188 paraffin wax Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 239000001944 prunus armeniaca kernel oil Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- MCRMUCXATQAAMN-HNNXBMFYSA-N (2s)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(O)C=C1 MCRMUCXATQAAMN-HNNXBMFYSA-N 0.000 description 3
- 102100038902 Caspase-7 Human genes 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 208000017442 Retinal disease Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 239000012752 auxiliary agent Substances 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000001151 peptidyl group Chemical group 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000017854 proteolysis Effects 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- CANZBRDGRHNSGZ-NSHDSACASA-N (2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 CANZBRDGRHNSGZ-NSHDSACASA-N 0.000 description 2
- ALZSTTDFHZHSCA-RNVDEAKXSA-N (4s)-4-[[(2s)-2-acetamido-3-carboxypropanoyl]amino]-5-[[(2s)-1-[[(2s)-3-carboxy-1-[(4-methyl-2-oxochromen-7-yl)amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC1=CC(=O)OC2=CC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(C)=O)C(C)C)=CC=C21 ALZSTTDFHZHSCA-RNVDEAKXSA-N 0.000 description 2
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- LYBWGROBJJXCJJ-VYIIXAMBSA-N 5-fluoro-3-[[(2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-4-oxopentanoic acid Chemical compound OC(=O)CC(C(=O)CF)NC(=O)[C@H](C(C)C)NC(=O)OCC1=CC=CC=C1 LYBWGROBJJXCJJ-VYIIXAMBSA-N 0.000 description 2
- 108010021160 Ac-aspartyl-glutamyl-valyl-aspartyl-aminomethylcoumarin Proteins 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 206010002329 Aneurysm Diseases 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 108090000567 Caspase 7 Proteins 0.000 description 2
- 102100038918 Caspase-6 Human genes 0.000 description 2
- 102000004225 Cathepsin B Human genes 0.000 description 2
- 108090000712 Cathepsin B Proteins 0.000 description 2
- 206010010144 Completed suicide Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 229920000832 Cutin Polymers 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- 102000005927 Cysteine Proteases Human genes 0.000 description 2
- 108010005843 Cysteine Proteases Proteins 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 240000007762 Ficus drupacea Species 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
- 206010061218 Inflammation Diseases 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 206010053159 Organ failure Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 208000037273 Pathologic Processes Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 102000013275 Somatomedins Human genes 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 206010052428 Wound Diseases 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000001367 artery Anatomy 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 235000013871 bee wax Nutrition 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 230000002498 deadly effect Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 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
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 2
- 229960003132 halothane Drugs 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000005534 hematocrit Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 230000009054 pathological process Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000012744 reinforcing agent Substances 0.000 description 2
- 230000008521 reorganization Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 206010040882 skin lesion Diseases 0.000 description 2
- 231100000444 skin lesion Toxicity 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- GAOCYGMWQJTKPG-UHFFFAOYSA-N tert-butyl 3-amino-5-fluoro-4-hydroxypentanoate Chemical compound CC(C)(C)OC(=O)CC(N)C(O)CF GAOCYGMWQJTKPG-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 230000026683 transduction Effects 0.000 description 2
- 238000010361 transduction Methods 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 150000003722 vitamin derivatives Chemical group 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 1
- IHPYMWDTONKSCO-UHFFFAOYSA-N 2,2'-piperazine-1,4-diylbisethanesulfonic acid Chemical compound OS(=O)(=O)CCN1CCN(CCS(O)(=O)=O)CC1 IHPYMWDTONKSCO-UHFFFAOYSA-N 0.000 description 1
- 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 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 description 1
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- KIZQNNOULOCVDM-UHFFFAOYSA-M 2-hydroxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].C[N+](C)(C)CCO KIZQNNOULOCVDM-UHFFFAOYSA-M 0.000 description 1
- HZLCGUXUOFWCCN-UHFFFAOYSA-N 2-hydroxynonadecane-1,2,3-tricarboxylic acid Chemical compound CCCCCCCCCCCCCCCCC(C(O)=O)C(O)(C(O)=O)CC(O)=O HZLCGUXUOFWCCN-UHFFFAOYSA-N 0.000 description 1
- SEBPXHSZHLFWRL-UHFFFAOYSA-N 3,4-dihydro-2,2,5,7,8-pentamethyl-2h-1-benzopyran-6-ol Chemical compound O1C(C)(C)CCC2=C1C(C)=C(C)C(O)=C2C SEBPXHSZHLFWRL-UHFFFAOYSA-N 0.000 description 1
- AUUIARVPJHGTSA-UHFFFAOYSA-N 3-(aminomethyl)chromen-2-one Chemical compound C1=CC=C2OC(=O)C(CN)=CC2=C1 AUUIARVPJHGTSA-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- RMPQWJZTCGUTRY-UHFFFAOYSA-N 3-amino-5-fluoro-4-hydroxypentanoic acid Chemical compound OC(=O)CC(N)C(O)CF RMPQWJZTCGUTRY-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- UMBVAPCONCILTL-MRHIQRDNSA-N Ac-Asp-Glu-Val-Asp-H Chemical compound OC(=O)C[C@@H](C=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(C)=O UMBVAPCONCILTL-MRHIQRDNSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000031104 Arterial Occlusive disease Diseases 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 229940124101 Caspase 3 inhibitor Drugs 0.000 description 1
- 108090000425 Caspase 6 Proteins 0.000 description 1
- 102100026549 Caspase-10 Human genes 0.000 description 1
- 102100032616 Caspase-2 Human genes 0.000 description 1
- 102100025597 Caspase-4 Human genes 0.000 description 1
- 102100026548 Caspase-8 Human genes 0.000 description 1
- 102000004039 Caspase-9 Human genes 0.000 description 1
- 108090000566 Caspase-9 Proteins 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 206010010947 Coordination abnormal Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 206010019899 Hereditary retinal dystrophy Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000983518 Homo sapiens Caspase-10 Proteins 0.000 description 1
- 101000867612 Homo sapiens Caspase-2 Proteins 0.000 description 1
- 101000933112 Homo sapiens Caspase-4 Proteins 0.000 description 1
- 101000741014 Homo sapiens Caspase-7 Proteins 0.000 description 1
- 101000983528 Homo sapiens Caspase-8 Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 108060001084 Luciferase Proteins 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 101710089759 Melanin-concentrating hormone receptor 2 Proteins 0.000 description 1
- 208000036626 Mental retardation Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010068871 Myotonic dystrophy Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 108010047956 Nucleosomes Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000007990 PIPES buffer Substances 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000010513 Stupor Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 108010066665 acetyl-aspartyl-glutamyl-valyl-aspartal Proteins 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 239000000808 adrenergic beta-agonist Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940040563 agaric acid Drugs 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- NUZWLKWWNNJHPT-UHFFFAOYSA-N anthralin Chemical compound C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O NUZWLKWWNNJHPT-UHFFFAOYSA-N 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 208000021328 arterial occlusion Diseases 0.000 description 1
- 150000001509 aspartic acid derivatives Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 239000003150 biochemical marker Substances 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003778 catagen phase Effects 0.000 description 1
- 101150055276 ced-3 gene Proteins 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011280 coal tar Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960002311 dithranol Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000008519 endogenous mechanism Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000010437 erythropoiesis Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- ZMMJGEGLRURXTF-UHFFFAOYSA-N ethidium bromide Chemical compound [Br-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CC)=C1C1=CC=CC=C1 ZMMJGEGLRURXTF-UHFFFAOYSA-N 0.000 description 1
- 229960005542 ethidium bromide Drugs 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000001105 femoral artery Anatomy 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001905 globus pallidus Anatomy 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 101150113725 hd gene Proteins 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 230000002607 hemopoietic effect Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000001261 hydroxy acids Chemical group 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 208000016290 incoordination Diseases 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000017532 inherited retinal dystrophy Diseases 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- VYQNWZOUAUKGHI-UHFFFAOYSA-N monobenzone Chemical compound C1=CC(O)=CC=C1OCC1=CC=CC=C1 VYQNWZOUAUKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- 201000000585 muscular atrophy Diseases 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000018901 negative regulation of programmed cell death Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 210000000633 nuclear envelope Anatomy 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 210000001623 nucleosome Anatomy 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 1
- 230000008816 organ damage Effects 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 238000002135 phase contrast microscopy Methods 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000012113 quantitative test Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- QHYQEYIFTIIWFH-UHFFFAOYSA-N tert-butyl 3-nitropropanoate Chemical compound CC(C)(C)OC(=O)CC[N+]([O-])=O QHYQEYIFTIIWFH-UHFFFAOYSA-N 0.000 description 1
- SKTPZQUACZEWTQ-UHFFFAOYSA-N tert-butyl 5-fluoro-4-hydroxy-3-nitropentanoate Chemical compound CC(C)(C)OC(=O)CC([N+]([O-])=O)C(O)CF SKTPZQUACZEWTQ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 210000000216 zygoma Anatomy 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P37/04—Immunostimulants
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/16—Sulfur atoms
-
- 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
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2810/00—Vectors comprising a targeting moiety
- C12N2810/40—Vectors comprising a peptide as targeting moiety, e.g. a synthetic peptide, from undefined source
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Psychology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Hospice & Palliative Care (AREA)
- Transplantation (AREA)
- Genetics & Genomics (AREA)
- Emergency Medicine (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Biochemistry (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Orthopedic Medicine & Surgery (AREA)
Abstract
本发明涉及通式(I)代表的新的二肽,其中R1-R3和AA如本文中所定义。本发明涉及一项发现,即:式(I)化合物是编程性细胞死亡的强抑制剂。因此,本发明的抑制剂可以在细胞、组织或整个器官发生损失的各种临床疾病中延缓或阻断细胞死亡。
Description
发明背景
发明领域
本发明为医药化学领域。具体地说,本发明涉及为编程性细胞死亡的强抑制剂的二肽。本发明还涉及这些二肽在降低或治疗编程性细胞死亡中的应用。
背景技术的描述
有机体通过不同地称作受控细胞死亡、程序细胞死亡或编程性细胞死亡的过程清除不需要的细胞。这种细胞死亡是动物发育以及组织内环境稳定和老化的正常状况(Glucksmann,A.,剑桥哲学协会的生物学评论(Biol.Rev.Cambridge Philos.Soc.)26:59-86(1951);Glucksmann,A.,生物学文献76:419-437(1965);Ellis等,发育(Dev.)112:591-603(1991);Vaux等,细胞76:777-779(1994))。编程性细胞死亡调节细胞数目,促进形态形成,去除有害或异常细胞并清除那些已完成其功能的细胞。另外,编程性细胞死亡会响应各种生理压力、诸如氧不足或局部缺血而发生(PCT公布的申请WO96/20721)。
经历受控细胞死亡的细胞有许多共有的形态学变化,包括胞浆和核膜起泡,细胞皱缩(核质和胞质浓缩),细胞器重新定位和压缩,染色质浓缩以及产生凋亡细胞体(含胞内物质的膜封闭颗粒)(Orrenius,S.,国际医学杂志237:529-536(1995))。
编程性细胞死亡是通过细胞自杀的内源性机理实现的(Wyllie,A.H.,生物学和病理学中的细胞死亡,Bowen和Lockshin编,Chapman和Hall出版(1981),9-34页)。因内部或外部信号的作用,细胞激活其内部编码的自杀程序。该自杀程序是通过精细调控的基因程序的活化而完成的(Wylie等,Int.Rev.Cyt.68:251(1980);Ellis等,细胞生物学年评7:663(1991))。凋亡细胞和细胞体通常在裂解前被邻近细胞或巨噬细胞识别并清除。由于这种清除机理,尽管有大量的细胞被清除,但并不会诱导炎症(Orrenius,S.,国际医学杂志237:529-536(1995))。
哺乳动物白介素-1β(IL-1β)在各种病理学过程中起着重要的作用,所述病理学过程包括慢性和急性炎症以及自身免疫疾病(Oppenheim,J.H.等,今日免疫学7:45-56(1986))。IL-1β是作为细胞相关前体多肽(IL-1β原)合成的,该IL-1β原不能结合IL-1受体,并且无生物学活性(Mosley等,生物化学杂志262:2941-2944(1987))。通过抑制IL-1β前体向成熟IL-1β的转化,就可以抑制白介素-1的活性。白介素-1β转化酶(ICE)是对白介素-1β(IL-1β)的活化起作用的蛋白酶(Thornberry,N.A.,等,自然356:768(1992);Yuan,J.等,细胞75:641(1993))。ICE是一种能裂解无活性白介素-1原产生成熟IL-1的底物特异性半胱氨酸蛋白酶。编码ICE和CPP32的基因是哺乳动物ICE/Ced-3基因家族中的成员,目前该基因家族包括至少12个成员:ICE,CPP32/Yama/Apopain,mICE2,ICE4,ICH1,TX/ICH-2,MCH2,MCH3,MCH4,FLICE/MACH/MCH5,ICE-LAP6和ICErelⅢ。这一半胱氨酸蛋白酶家族的蛋白水解活性在细胞死亡的介导中显得很关键,它们的活性位点半胱氨酸残基是ICE介导的编程性细胞死亡必需的(Miura等,细胞75:653-660(1993))。最近,该基因家族已被命名为caspases(Alnernri,E.S.等,细胞87:171(1996))。
IL-1也是一种参与介导广泛生物学应答的细胞因子,所述生物应答包括炎症、败血症性休克、伤口愈合、血细胞生成和某些白血病生长(Dinarello,C.A.,血液77:1627-1652(1991);diGiovine等,今日免疫学11:13(1990))。
现已基于caspases的肽底物结构制备了许多强caspases抑制剂。然而,与它们的体外强效能相反,还未报道有对编程性细胞死亡完整细胞模型具有良好功效(IC50<1μM)的抑制剂(Thornberry,N.A.,化学生物学(Chem.Biol.)5:R97-103(1998))。因此,需要能在编程性细胞死亡的完整细胞模型中显示出功效(IC50<1μM)并且在编程性细胞死亡的动物模型中有效的细胞死亡抑制剂。这些抑制剂可以用作治疗剂,用于治疗其中受控细胞死亡和IL-1的细胞因子活性起作用的疾病状态。
WO93/05071公开了肽ICE抑制剂,其结构式为:
Z-Q2-Asp-Q1其中Z是N-末端保护基;Q2为0-4个氨基酸,使得序列Q2-Asp相当于序列Ala-Tyr-Val-His-Asp的至少一部分;Q1包含负电性离去基。示范性的二肽是Boc-His-Asp-CH2F,Boc-Tyr-Asp-CH2F,Boc-Phe-Asp-CH2F,Ac-His-Asp-CH2F,Ac-Tyr-Asp-CH2F,Ac-Phe-Asp-CH2F,Cbz-His-Asp-CH2F,Cbz-Tyr-Asp-CH2F和Cbz-Phe-Asp-CH2F。
美国专利5,585,357公开了作为ICE抑制剂的肽酮,其结构式为:其中n为0-2;AA各自独立地为L-缬氨酸或L-丙氨酸;R1选自N-苄氧基羰基和其他基团;R8、R9、R10各自独立地为氢、低级烷基和其他基团。
Revesz等(四面体快报35:9693-9696,1994)报道了作为相应酸的药物前体的乙酯三肽的制备:所述相应酸是一种强ICE抑制剂。
发明概述
其中R1是N-末端保护基;AA是任何天然α-氨基酸的残基、或β-氨基酸;R2是H或CH2R4,其中R4是负电性离去基;R3是烷基或H,条件是AA不为His、Tyr、Pro或Phe。
本发明涉及一项发现,即:尽管式Ⅰ代表的二肽基caspase抑制剂在酶试验中显示对酶的效力比三肽和四肽抑制剂低,但却在基于细胞的系统中令人惊奇地显示为编程性细胞死亡的强抑制剂。这些化合物在小鼠肝编程性细胞死亡模型中表现出体内系统活性并且是抗Fas诱导致死的强抑制剂,在缺血性中风大鼠模型中,显示出强的神经保护作用。
本发明还涉及本发明的二肽在减轻、预防或治疗其中编程性细胞死亡是致病因素或是其结果的疾病中的应用。本发明应用的实例包括:在病灶局部缺血和普遍缺血后保护神经系统;治疗神经变性疾病,诸如早老性痴呆、杭廷顿氏舞蹈病、朊病毒疾病、帕金森氏症、多发性硬化、肌萎缩性侧索硬化、共济失调、毛细管扩张和脊髓延髓萎缩;治疗心脏病,包括心肌梗塞、充血性心力衰竭和心肌病;治疗视网膜疾病;治疗自身免疫疾病,包括红斑狼疮、类风湿性关节炎、Ⅰ型糖尿病、斯耶格伦氏综合征和肾小球性肾炎;治疗多囊肾病和贫血/红细胞生成;治疗免疫系统疾病,包括AIDS和SCIDS;在移植过程中减少或预防细胞、组织和器官损伤;在工业化生物工程中减少或预防细胞系死亡;减少或预防脱发(毛发损失);以及减少皮肤细胞的过早死亡。
本发明提供了一种药物组合物,它包含能减少动物的编程性细胞死亡的有效量的式Ⅰ化合物。
本发明还提供了用于哺乳动物器官或组织的防腐或储存的溶液,或用于哺乳动物或酵母细胞的生长介质,其中在所述溶液或生长介质中包含了有效量的式Ⅰ化合物,以减少所述器官、组织或细胞的编程性细胞死亡。
附图的简要描述
图1A-1G分别显示了用环己酰胺(CHX)和DMSO刺激(图1A)、用肿瘤坏死因子-α(TNF-α)/CHX和DMSO刺激(图1B)、用50μMBOC-Asp(OMe)-CH2F,TNF-α/CHX刺激(图1C)、用50μM Cbz-Val-Asp(OMe)-CH2F,TNF-α/CHX刺激(图1D)、用50μM Cbz-Glu(OMe)-Val-Asp(OMe)-CH2F,TNF-α/CHX刺激(图1E)、用50μMCbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F,TNF-α/CHX刺激(图1F)、和用DMSO刺激(图1G)的Hela细胞的照片。
图2A-2G分别显示了用环己酰胺(CHX)和DMSO刺激(图2A)、用TNF-α/CHX和DMSO刺激(图2B)、用5μM BOC-Asp(OMe)-CH2F,TNF-α/CHX刺激(图2C)、用5μM Cbz-Val-Asp(OMe)-CH2F,TNF-α/CHX刺激(图2D)、用5μM Cbz-Glu(OMe)-Val-Asp(OMe)-CH2F,TNF-α/CHX刺激(图2E)、用5μM Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F,TNF-α/CHX刺激(图2F)、和用DMSO刺激(图2G)的Hela细胞的照片。
图3A-3G分别显示了用环己酰胺(CHX)和DMSO刺激(图3A)、用TNF-α/CHX和DMSO刺激(图3B)、用0.5μM BOC-Asp(OMe)-CH2F,TNF-α/CHX刺激(图3C)、用0.5μM Cbz-Val-Asp(OMe)-CH2F,TNF-α/CHX刺激(图3D)、用0.5μM Cbz-Glu(OMe)-Val-Asp(OMe)-CH2F,TNF-α/CHX刺激(图3E)、用0.5μM Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F,TNF-α/CHX刺激(图3F)、和用DMSO刺激(图3G)的Hela细胞的照片。
图4是一个条形图,显示了各种浓度的Cbz-Val-Asp(OMe)-CH2F(a)与各种浓度的Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F(b)相比,保护Hela细胞免受TNF-α/CHX侵害的情况。
图5是一个条形图,显示了各种浓度的Cbz-Val-Asp(OMe)-CH2F(a)和BOC-Asp(OMe)-CH2F(b)保护Hela细胞免受TNF-α/CHX侵害的情况。
图6显示了各种低剂量的Cbz-Val-Asp(OMe)-CH2F(a)与各种低剂量的Cbz-Val-Ala-Asp(OMe)-CH2F(b)相比,保护Hela细胞免受TNF-α/CHX侵害的情况。
图7A-7E显示了Jurkat细胞的PARP裂解试验结果。化合物1=Cbz-Val-Asp(OMe)-CH2F,化合物2=Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F,化合物3=Cbz-Glu(OMe)-Val-Asp(OMe)-CH2F,化合物4=Cbz-Ile-Glu(OMe)-Thr-Asp(OMe)-CH2F,化合物5=BOC-Asp(OMe)-CH2F,化合物6=Cbz-Asp-α-([2,6-二氯苯甲酰氧基]甲基酮),化合物7=Cbz-Val-Ala-Asp(OMe)-CH2F。
图8A和8B是PARP裂解的照片,显示了Z-VD-fmk和Z-VAD-fmk对用抗Fas处理的Jurkat细胞的PARP裂解的抑制。
图9是存活细胞比Z-VD-fmk浓度图,显示了Z-VD-fmk对TNF-α诱导的细胞死亡的抑制。
图10是DNA梯状化的照片,显示了Z-VD-fmk对用抗Fas处理的Jurkat细胞的DNA梯状化的抑制。
图11A和11B显示了系统给药的Cbz-Val-Asp-CH2F对瞬时病灶局部缺血大鼠模型的神经保护作用。瞬间病灶局部缺血2.25小时和再灌注22小时后,定量测量皮质梗塞的体积。
发明的详细描述
R1是N-末端保护基,包括叔丁氧基羰基、乙酰基和苄氧基羰基;AA是任何天然α-氨基酸的残基、或β-氨基酸,例如:Gly,Thr,Glu,Lys,Arg,Ser,Asn,Gln,Val,Ala,Leu,Ile,Met,和β-氨基酸诸如β-Ala,但它们不是His,Tyr,Pro或Phe;R2是H或CH2R4,R4是负电性离去基诸如F、Cl、TsO-、MeO-、ArO-、ArCOO-、ArN-和ArS-;R3是烷基或H。
关于R3,优选的烷基是C1-6烷基,例如:甲基、乙基、丙基、异丙基、异丁基、戊基和己基。
本发明涉及一项发现,即:尽管式Ⅰ代表的二肽基caspase抑制剂对酶的效力比三肽和四肽抑制剂低,但令人惊奇地是基于细胞的系统中的编程性细胞死亡的强抑制剂。这些化合物在小鼠肝编程性细胞死亡模型中表现出体内系统活性并且是抗Fas-诱导致死的强抑制剂,在缺血性中风大鼠模型中,显示出强的神经保护作用。这些抑制剂将在与细胞、组织或整个器官发生损失有关的多种临床疾病中和工业应用中减慢或阻断细胞死亡。因此,本发明还涉及其中编程性细胞死亡起作用的疾病的治疗、预防或减少方法。这些疾病将在下文中更全面描述。
所述方法包括给予需要这种治疗的动物能抑制编程性细胞死亡的有效量的本发明抑制剂,或其药学上可接受的盐或药物前体。
优选的R1是叔丁氧基羰基、乙酰基和苄氧基羰基。优选的R3是H、Me、Et或t-Bu。优选的AA是Val、Ala、Leu、Ile、Met和β-氨基酸诸如β-Ala。
例举的优选的式Ⅰ表示的编程性细胞死亡抑制剂包括但不限于:
Boc-Ala-Asp-CH2F,
Boc-Val-Asp-CH2F,
Boc-Leu-Asp-CH2F,
Ac-Val-Asp-CH2F,
Ac-Ile-Asp-CH2F,
Ac-Met-Asp-CH2F,
Cbz-Val-Asp-CH2F,
Cbz-β-Ala-Asp-CH2F,
Cbz-Leu-Asp-CH2F,
Cbz-Ile-Asp-CH2F,
Boc-Ala-Asp(OMe)-CH2F,
Boc-Val-Asp(OMe)-CH2F,
Boc-Leu-Asp(OMe)-CH2F,
Ac-Val-Asp(OMe)-CH2F,
Ac-Ile-Asp(OMe)-CH2F,
Ac-Met-Asp(OMe)-CH2F,
Cbz-Val-Asp(OMe)-CH2F,
Cbz-β-Ala-Asp(OMe)-CH2F,
Cbz-Leu-Asp(OMe)-CH2F,和
Cbz-Ile-Asp(OMe)-CH2F.
本发明的某些化合物可以作为立体异构体包括旋光异构体存在。本发明包括所有立体异构体和这些立体异构体的消旋混合物以及可以按照本领域普通技术人员熟知的方法分离的单独的对映体。
药学上可接受的加成盐的实例包括无机和有机酸加成盐,诸如盐酸盐、氢溴化物、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐。
药物前体的实例包括其中R3是烷基或取代烷基(诸如CH2OCH3)的式Ⅰ-Ⅱ化合物。另外,当AA含有羧酸基团时,其中R3为H的式Ⅰ-Ⅱ的药物前体的实例包括其中一个羧基被酯化或两个羧基均被酯化(例如被C1-6醇酯化)或者相应的酰胺形式(例如与C1-6胺形成)的化合物。
本发明还涉及对于遭受编程性细胞死亡之苦的动物中编程性细胞死亡的抑制有响应的疾病的治疗方法。用于本发明方法的特别优选的化合物的实施方案是前面所定义的式Ⅱ代表的化合物。
本发明的化合物可以利用本领域技术人员公知的方法制备。具体而言,式Ⅰ-Ⅱ化合物可以按照方案1中举例说明的反应进行制备。按照Revesz等的方法(四面体快报35:9693-9696,1994)制备中间产物1。1与N-保护的氨基酸如Z-Val-OH偶合得到酰胺2,按照Revesz等的方法(四面体快报35:9693-9696,1994)用Dess-Martin试剂将2氧化得到3。该酯通过酸催化裂解得到游离酸4,再将4转化为酯5。
本发明的一个重要方面在于发现了式Ⅰ-Ⅱ化合物是编程性细胞死亡的强抑制剂。因此,预期这些抑制剂能在细胞、组织或整个器官发生损失的各种临床疾病中减慢或阻断细胞死亡。
本发明细胞死亡抑制剂可以在各种局部缺血和兴奋毒性疾病中用于减少或预防神经系统(脑、脊髓和周围神经系统)的细胞死亡,所述疾病包括但不限于因中风导致的病灶局部缺血和因心搏停止导致的普遍缺血。一个特定的用法是用于治疗高危分娩中新生儿出生过程中可能出现的缺氧。这些细胞死亡抑制剂还可以用于减少或预防因外伤性损伤(诸如头部创伤)、病毒感染或辐射诱导的神经细胞死亡(例如,作为癌症放疗的副作用)等导致的神经系统的细胞死亡。这些细胞死亡抑制剂还可以用于减少或预防神经变性疾病范围内的细胞死亡,所述疾病包括但不限于早老性痴呆、杭廷顿氏舞蹈病、帕金森氏症、多发性硬化、肌萎缩性侧索硬化和脊髓延髓萎缩。本发明细胞死亡抑制剂的体内神经保护性能可以用瞬时病灶局部缺血大鼠模型检验(Xue等,中风21:166(1990))。
本发明细胞死亡抑制剂可以用于预防可能导致心肌死亡的任何疾病中的细胞死亡。这些疾病包括心肌梗塞、充血性心力衰竭和心肌病。一个特定的应用是用于减少或预防心脏因某些病毒感染时发生的心肌细胞死亡。
本发明细胞死亡抑制剂的体内活性可以利用Rodriguez等(Rodriguez等,实验医学杂志184:2067-2072(1996))描述的“小鼠肝编程性细胞死亡”模型进行检验。在该模型中,给小鼠静脉注射(Ⅳ)抗Fas抗体,该抗体能诱导肝脏和其他器官中大面积的编程性细胞死亡,从而导致普遍性器官衰竭和死亡。可以用该模型间接测试本发明细胞死亡抑制剂的系统性生物可利用率,以及它们的体内抗编程性细胞死亡性能。
本发明细胞死亡抑制剂可以用于预防眼内压升高疾病(诸如青光眼)或与老化过程有关的视网膜疾病(诸如年龄相关性黄斑变性)中可能发生的视网膜神经元的细胞死亡。这些抑制剂还可用于治疗遗传性视网膜变性疾病,诸如色素性视网膜炎。
本发明细胞死亡抑制剂还可用于减少或预防免疫系统细胞的过早死亡,特别是用于治疗免疫缺陷疾病,诸如获得性免疫缺陷综合征(AIDS),重症联合免疫缺陷综合征(severe combined immunedeficiency syndrome,SCIDS)及相关疾病。这些细胞死亡抑制剂还可用于治疗辐射诱导的免疫抑制。
人的器官和组织移植是器官衰竭中常用的治疗方法。然而,在移植处置过程中,供体器官或组织有发生细胞死亡的危险,因为它们在植入宿主之前失去了正常的血液供给。这种局部缺血状态可以通过给供体器官或组织输注细胞死亡抑制剂来进行治疗,或者通过将细胞死亡抑制剂直接加入到器官/组织储存介质中来进行治疗。细胞死亡抑制剂也可以用于减少或预防移植后供体器官/组织的细胞死亡,以保护它们不受通过触发编程性细胞死亡来杀死其目标的宿主免疫细胞的杀死作用。细胞死亡抑制剂的细胞保护作用还可用于预防体外授精过程中应用的人或动物精液和卵的死亡。这些抑制剂可以在收获过程中使用,也可以包括在储存介质中。
哺乳动物细胞系和酵母细胞常用于生产大量工业或药用的重组蛋白质(诸如抗体、酶或激素)。由于生长条件、所表达的重组分子的性质(一些是有毒的)以及其他未知因素的影响,有一些这样的细胞系的有效期限是有限的。通过在生长基中加入10-200mM浓度的细胞死亡抑制剂可以延长工业细胞系的有效期限。
调节毛发生长和损失的因素大多不明。然而,有一些证据表明,毛囊退化(称为毛发生长中期)至少部分可归因于编程性细胞死亡。因此,预期本发明的细胞死亡抑制剂可用于治疗因各种疾病引起的脱发,所述疾病包括但不限于男性模式秃发、辐射诱导或化疗诱导的脱发、以及因情绪压力导致的脱发。还有证据表明,编程性细胞死亡在发色的减退中起作用。因此,预期本发明细胞死亡抑制剂还可用于治疗或预防头发过早斑白的情况。
接触高水平的辐射、热或化学物质后可发生皮肤上皮细胞死亡。预期本发明的细胞死亡抑制剂可用于治疗、减少或预防这种类型的皮肤损害。在一个特定的应用中,这些细胞死亡抑制剂可以以软膏的形式用于治疗皮肤严重阳光照射过度并预防皮肤起疱和脱皮。
Goldberg等(自然遗传学13:442-449(1996))最近报道,杭廷顿氏舞蹈病(HD)基因的蛋白产物-杭廷顿素(huntingtin)可以被CPP32而不是ICE裂解。HD中的突变是HD基因5’末端的CAG三核苷酸的扩展。该三核苷酸扩展超过36次重复与HD的临床表现有关。CAG扩展促进了杭廷顿素被CPP32裂解,因此在HD中将CPP32的作用与编程性细胞死亡联系起来。本发明的具有CPP32抑制活性的化合物将可用于阻断CPP32诱导的编程性细胞死亡,由此预防和治疗HD以及其他以三核苷酸重复区的扩展为特征的疾病,诸如肌强直性营养不良、脆性X精神发育迟缓、脊髓延髓性肌萎缩、Ⅰ型脊髓小脑性共济失调和齿状核-红核苍白球丘脑下核萎缩。
本发明范围内的组合物包括其中包含本发明化合物的所有组合物,本发明化合物在其中的量足以达到其预期目的。尽管个体的需要不相同,但每种组份的最佳有效量范围的确定是本领域中的常规技术。一般说来,对哺乳动物例如人给药的化合物的口服剂量是0.0025-50mg/kg体重/天,或者是相当量的其药学上可接受的盐,体重是指进行治疗的患有编程性细胞死亡介导的疾病的哺乳动物的体重,所述疾病是例如神经细胞死亡、心脏病、视网膜疾病、多囊肾病和免疫系统疾病。优选以约0.01-约10mg/kg的量口服给药,用于预防或治疗这些疾病。对于肌内注射来说,剂量一般是口服剂量的约二分之一。例如,治疗或预防神经细胞死亡时,合适的肌内注射剂量应当是约0.0025-约15mg/kg,最优选为约0.01-约10mg/kg。
单位口服剂量可以包含约0.01-约50mg、优选约0.1-约10mg化合物。单位剂量可以作为一个或多个片剂每天给药一次或多次,每片中含有约0.1-约10、通常为约0.25-50mg化合物或其溶剂化物。
除了作为生药给药该化合物以外,本发明化合物也可以作为含有合适的药学上可接受载体的药物制剂的一部分给药,所述载体包含有助于这些化合物加工成可药用制剂的赋形剂和助剂。优选的是,这些制剂,特别是可口服给药并可用于优选给药类型的那些制剂诸如片剂、糖衣丸和胶囊、可直肠给药的制剂诸如栓剂、以及通过注射或口服给药的合适的溶液剂,它们含有约0.01-99%、优选约0.25-75%的活性物质,和赋形剂。
本发明范围内还包括本发明化合物的无毒的药学上可接受的盐。将本发明的特定细胞死亡抑制剂的溶液与药学上可接受的无毒酸的溶液混合可形成酸加成盐,所述无毒酸是诸如盐酸、富马酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、磷酸、草酸,等等。将本发明的特定细胞死亡抑制剂的溶液与药学上可接受的无毒碱的溶液混合可形成碱性盐,所述无毒碱是诸如氢氧化钠、氢氧化钾、氢氧化胆碱、碳酸钠等。
本发明的药物组合物可以对能体验到本发明化合物有益效果的任何动物给药。这些动物中最重要的是哺乳动物,例如人,虽然本发明并不欲被局限在此。
本发明药物组合物可以用能达到其预期目的的任何方式给药。例如,可以通过胃肠外、皮下、静脉内、肌内、腹膜内、经皮的、面颊、鞘内或颅内途径给药。另外,或者并行地,可以通过口服途径给药。给药剂量将取决于接受者的年龄、健康状况和体重、并行治疗的种类(如果有的话)、治疗的频率、以及预期效果的性质。
本发明的药物制剂用已知方式制备,例如,利用常规的混合、制粒、包糖衣、溶解、或冷冻干燥方法。因此,口服的药物制剂可以用下述方法得到:将活性化合物与固体赋形剂混合,可选地研磨该所得混合物并加工该混合物颗粒,之后如果期望或需要的话,加入合适的助剂,由此制得片剂或糖衣丸芯。
合适的赋形剂尤其是填充剂,诸如糖类,例如乳糖或蔗糖,甘露糖醇或山梨糖醇,纤维素制剂和/或磷酸钙,例如磷酸三钙或磷酸氢钙,以及粘合剂诸如淀粉糊,例如使用玉米淀粉、小麦淀粉、稻米淀粉、马铃薯淀粉,明胶,黄芪胶,甲基纤维素,羟丙基甲基纤维素,羧甲基纤维素钠,和/或聚乙烯吡咯烷酮。如果需要,也可以加入崩解剂,诸如上面所提到的淀粉以及羧甲基淀粉,交联聚乙烯吡咯烷酮,琼脂,或藻酸或其盐,诸如藻酸钠。助剂尤其是流速调节剂和润滑剂,例如二氧化硅,滑石,硬脂酸或其盐,诸如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。糖衣丸芯包上合适的包衣,如果需要,该包衣是抗胃液的。出于此目的,可以使用浓糖溶液,它可以可选地含有阿拉伯树胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆溶液以及合适的有机溶剂或溶剂混合物。为了制备抗胃液的包衣,可使用合适的纤维素制剂诸如乙酰纤维素邻苯二甲酸酯或羟丙基甲基纤维素邻苯二甲酸酯的溶液。例如,为了识别或为了描绘活性化合物剂量的组合特性,可以向片剂或糖衣丸包衣中加入染料或色素。
其他可口服使用的药物制剂包括明胶制成的推入配合式胶囊,以及由明胶和增塑剂诸如甘油和山梨醇制成的密封软胶囊。推入配合式胶囊可以含有颗粒形式的活性化合物,这些颗粒可以与填充剂诸如乳糖、粘合剂诸如淀粉、和/或润滑剂诸如滑石或硬脂酸镁以及可选地与稳定剂混合。在软胶囊中,活性化合物优选溶解或悬浮于适当的液体中,诸如脂肪油或液体石蜡。此外可以加入稳定剂。
可经直肠使用的可能的药物制剂包括,例如栓剂,它由一种或多种活性化合物的组合物以及栓剂基质组成。合适的栓剂基质是,例如天然或合成甘油三酯,或石蜡烃。此外,也有可能使用由活性化合物与基质的混合物组成的明胶直肠胶囊。可能的基质材料包括,例如液体甘油三酯、聚乙二醇、或石蜡烃。
合适的胃肠外给药的制剂包括水溶性形式的活性化合物的水溶液,例如,水溶性盐和碱溶液。可以加入缓冲液例如Tris。另外,也可以作为适宜的油性注射用悬液形式的活性化合物悬液给药。合适的亲脂性溶剂或载体包括脂肪油,例如芝麻油,或合成脂肪酸酯,例如油酸乙酯或甘油三酯或聚乙二醇-400(化合物可溶于PEG-400)。含水注射用悬液可以含有能提高该悬液粘度的物质,包括例如羧甲基纤维素钠、山梨醇、和/或葡聚糖。可选地,该悬液还可含有稳定剂。
根据本发明的一个方面,本发明化合物以局部和胃肠外制剂形式使用,并用于治疗皮肤损伤,诸如因接触高水平的辐射,包括紫外线照射、热或化学物质引起的。
该组合物中还可加入对皮肤有治疗作用的一种或多种附加物质。因此,该组合物还可含有一种或多种能升高皮肤中环腺苷酸浓度的化合物。合适的化合物包括约0.1-1%的腺苷或核酸水解产物,和约0.5-5%的罂粟碱,二者均是基于组合物重量而言的重量百分数。约0.1-2%的β-肾上腺素能兴奋剂诸如异丙肾上腺素,或约0.1-1%的环腺苷酸也是合适的,这二者也是基于组合物重量而言的重量百分数。可以加入到本发明组合物中的其他合适的附加活性成分的类型包括已知对皮肤具有有益效果的任何化合物。这样的化合物包括约0.003-0.3重量%的视黄类物质(retinoid)诸如维生素A,和约0.1-10重量%的色原烷醇诸如维生素E或其衍生物,二者均基于组合物重量。此外,在化妆品组合物中可以加入抗炎剂和角质成形剂(keratoplastic agent)。典型的抗炎剂是诸如约0.25-5重量%的氢化可的松或其醋酸盐之类的皮质类固醇,或诸如约0.025-0.5重量%的地塞米松之类的皮质类固醇,二者均基于组合物的重量。典型的角质成形剂是约0.1-20重量%的煤焦油或约0.05-2重量%的蒽地酚,二者均基于组合物重量。
通过选择适宜的载体,本发明的局部用组合物优选配制成油剂、膏霜、洗液、油膏等。合适的载体包括植物油或矿物油,白凡士林(白软石蜡),支链脂肪或油,动物脂肪以及高分子量醇(大于C12)。优选的载体是可溶解活性成分的那些。如果需要,还可以包括乳化剂、稳定剂、湿润剂和抗氧剂,以及可以产生颜色或香味的试剂。另外,在这些局部用制剂中可以使用经皮渗透增强剂。在美国专利3,989,816和4,444,762中可以找到这种增强剂的例子。
膏霜优选用矿物油、自乳化蜂蜡和水的混合物制备,在该混合物中混合有溶解于少量油诸如杏仁油中的活性成分。这种膏霜的一个典型实例是包括约40份水、约20份蜂蜡、约40份矿物油和约1份杏仁油的膏霜。
油膏可以用下述方法制备:将活性成分在植物油诸如杏仁油中的溶液与温热软石蜡混合并使该混合物冷却。这种油膏的一个典型实例是包括约30重量%的杏仁油和约70重量%的白色软石蜡的油膏。
洗液可以用下述方法方便制备:将活性成分溶解于合适的高分子量醇诸如丙二醇或聚乙二醇中。
另外,这些组合物中可以包括本领域技术人员公知或明了的其他药剂、生长因子、伤口密封剂、载体等。本发明组合物对已遭受皮肤损伤诸如烧伤的温血动物诸如人给药,其用量足以使宿主的愈合过程比未经治疗时进展得更快。关于这种用途的有效量将取决于所治疗患者的皮肤损害的严重程度以及该患者的一般健康状态。长期应用的维持剂量可以根据需要进行调整。对于兽医用途来说,可以根据需要以更高的浓度给药。
当动物的毛发生长减少时,本发明组合物以足以提高毛发生长速率的量给药。关于这种用途的有效量将取决于所治疗患者的毛发生长减少的程度,以及该患者的一般健康状态。长期应用的维持剂量可以根据需要进行调整。对于兽医用途来说,可以根据需要以更高的水平给药。
以下实施例说明而不限制本发明的方法和组合物。临床治疗中正常遇到的各种条件和参数的其他适当的改进和变化以及对本领域技术人员来说显而易见的各种改进和变化均在本发明的实质和范围内。
实施例1
5-氟-4-羟基-8-硝基戊酸叔丁酯
将存在于干燥CH2Cl2(100mL)中的草酸(1.9mL,21.8mmol)溶液冷却至-78℃,边搅拌边加入存在于干燥CH2Cl2(10mL)中的DMSO(3.0mL,42.3mmol)溶液,加入速率应使温度保持在-50℃--60℃。搅拌5分钟后,加入存在于干燥CH2Cl2(10mL)中的2-氟乙醇(1.2mL,18.4mmol)溶液,继续搅拌15分钟,然后加入干燥Et3N(13.5mL)。该反应混合物搅拌15分钟,然后使其恢复到室温。向该反应混合物中加入3-硝基丙酸叔丁酯(2.87g,16.38mmol)的CH2Cl2溶液(20mL)。该反应混合物在室温下搅拌3小时,然后倒入水(100mL)中。分离有机层,水层用CH2Cl2(2×50mL)萃取。该CH2Cl2溶液用盐水洗涤、干燥并蒸发。残余物用硅胶柱色谱法(己烷-EtOAc,7∶3)纯化两次,得到950mg(24.5%)标题产物,为无色粘性油。1H NMR(CDCl3),1.450(s,9H),2.80-2.90(m,2H),3.12-3.20(m,1H),4.41-4.59(m,2H),4.57-4.59(m,1H),4.95-5.01(m,1H).
实施例2
3-氨基-5-氟-4-羟基-戊酸叔丁醇
向5-氟-4-羟基-3-硝基戊酸叔丁酯(950mg,4.0mmol)的MeOH溶液(20mL)中加入阮内镍(约200mg),该混合物在室温和H2(30-35psi)下振摇18小时。将其过滤,催化剂用MeOH(2×10mL)洗涤。将MeOH溶液蒸发,残余物用硅胶柱色谱法纯化(EtOAc-MeOH,10∶1),得到840mg(96%)标题化合物,为淡黄色粘性油。1H NMR(CDCl3),1.450(s,9H),2.12(bs,3H,OH和NH2),2.28-2.38(m,1H),2.47-2.57(m,1H),3.24-3.30(m,1H),3.54-3.76(m,1H),4.38-4.48(m,1H),4.54-4.61(m,1H).
实施例3
3-(Cbz-Va1-酰胺基)-5-氟-4-羟基-戊酸叔丁酯
向Cbz-缬氨酸(396mg,1.58mmol)的THF溶液(20mL)中加入EDCl(300mg,1.57mmol)、HOBT(240mg,1.57mmol)和DMAP(129mg,1.06mmol)。所得混合物搅拌5分钟,然后加入3-氨基-5-氟-4-羟基-戊酸叔丁酯(215mg,1.04mmol)的THF溶液(10mL),并将其在室温下搅拌18小时。将混合物过滤,蒸发THF溶液,残余物用硅胶柱色谱法纯化(己烷-EtOAc,3∶2),得到290mg(68%)标题化合物,为白色固体。 1HNMR(CDCl3),0.905(d,3H,J=7),0.965(d,3H,J=7),1.428(s,9H),2.07-2.16(m,1H),2.50-2.57(m,1H),2.64-2.70(m,1H),3.52(bs,1H,OH),3.92-3.96(m,2H),4.20-4.27(m,1H),4.40(bs,1H),4.49(bs,1H),5.10(s,2H),5.31-5.4(m,1H,NH),6.86-6.93(m,1H,NH),7.350(s,5H).
实施例4
Z-Val-Asp-Fmk叔丁酯
向periodinane(485mg,1.14mmol)的CH2Cl2乳液(imussion)(20mL)中加入3-(Cbz-Val-酰胺基)-5-氟-4-羟基-戊酸叔丁酯(230mg,0.52mmol)的CH2Cl2溶液(12mL),所得白色混合物在室温下搅拌40分钟,然后倒入25mL含有1.26g(8mmol)Na2S2O3的饱和NaHCO3水溶液中。所得混合物搅拌20分钟,将所得澄清CH2Cl2溶液分离,水层用CH2Cl2(2×25mL)萃取。CH2Cl2溶液用盐水洗涤并蒸发,残余物用硅胶柱色谱法纯化(己烷-EtOAc,3∶2),得到190mg(83%)标题化合物,为白色固体。1HNMR(CDCl3),0.91-0.97(m,6H),1.415(s,9H),2.10-2.20(m,1H),2.70-2.77(m,1H),2.95-3.01(m,1H),3.98-4.06(m,1H),4.87-5.28(m,6H),6.95-7.01(m,1H),7.350(s,5H).
实施例5
Z-Val-Asp-fmk
向Z-Val-Asp-fmk叔丁酯(180mg,0.41mmol)的干燥CH2Cl2溶液(5mL)中加入F3CCO2H(1.0mL),其在室温下搅拌40分钟,然后蒸发。残余物用硅胶柱色谱法纯化(EtOAc-MeOH,10∶1),得到120mg(76%)标题化合物,为白色固体。 1HNMR(DMSO-d6),0.81-0.84(m,6H),1.87-1.96(m,1H),2.47-2.67(m,2H),3.77-3.87(m,1H),4.47-4.59(m,1H),4.91-5.16(m,4H),7.25-7.42(s,5H),8.40-8.49(m,1H).
利用实施例3-5中描述的相同方法制得下列化合物:
实施例6
Z-Leu-Asp-fmk
白色固体。1H NMR(CDCl3),0.87(m,6H),1.11(m,1H),1.47(m,1H),1.81(m,1H),2.7(m,1H),2.95(m,1H),4.10(m,1H),4.80-5.20(m,6H),7.31(s,5H).
实施例7
Z-Ile-Asp-fmk
白色固体。1H NMR(CDCl3),0.85-0.96(m,6H),1.14-1.26(m,1H),1.422(s,9H),1.87-2.04(m,1H),2.70-2.77(m,2H),2.93-3.00(m,1H),4.02-4.13(m,1H),4.80-5.30(s,6H),6.96(m,1H),7.35(s,5H).
实施例8
Z-Ala-Asp-fmk
白色固体。1H NMR(DMSO-d6),1.160(d,3H,J=7),2.54-2.70(m,2H),4.00(m,1H),4.54(m,1H),5.10-5.30(m,3H),7.235(s,5H),8.46-8.52(m,1H).
实施例9
Ac-Val-Asp-fmk
白色固体。1H NMR(DMSO-d6),0.80-0.84(m,6H),1.85-1.97(m,4H),2.56-2.75(m,2H),4.00-4.45(m,4H),5.00-5.30(m,2H),7.85-8.00(m,1H),8.53-8.60(m,1H).
实施例10
Z-N-Me-Val-Asp-fmk
白色固体。1H NMR(DMSO-d6),0.765(d,3H J=7),0.832(d,3H,J=7),2.06(m,1H),2.57-2.85(m,5H),4.21(m,1H),4.63(m,1H),5.02-5.18(m,4H),7.337(s,5H),8.850(m,1H).
实施例11
Z-Ala-Asp-fmk
白色固体。1H NMR(DMSO-d6),2.30(t,2H,J=7),2.48-2.70(m,3H),3.17(m,2H),4.41-4.60(m,2H),4.98-5.30(m,3H),5.40(m,1H),6.63(m,1H),7.32(s,5H),8.52(m,1H).
实施例12
Z-Gly-Asp-fmk
白色固体。1H NMR(DMSO-d6),12.50(s,1H),8.49(m,1H),7.52(m,1H),7.33(s,5H),5.08-5.25(m,1H),5.01(s,2H),4.10(m,1H),3.63(d,J=6.0Hz,2H),2.50-2.80(m,2H).
实施例13
Z-Phe-Asp-fmk
白色固体。1H NMR(DMSO-d6),8.60(m,1H),7.60(m,1H),7.24-7.30(m,10H),4.92(m,3H),4.60(m,1H),4.28(m,1H),2.90(m,2H),2.70(m,2H).
实施例14
Z-Glu-Asp-fmk
白色固体。1H NMR(DMSO-d6),12.20(m,1H),8.48(m,1H),7.56(m,1H),7.34(m,5H),5.12(m,1H),5.01(s,2H),4.51(m,1H),3.95(m,1H),2.71(m,2H),2.24(m,2H),1.72-1.82(m,2H).
实施例15
Z-Pro-Asp-fmk
白色固体。1H NMR(CD3OD):7.36-7.33(m,5H),5.13-5.11(m,2H),4.30(s,1H),3.58-3.50(m,2H),2.77-2.64(m,2H),2.24(m,1H),1.94(s,2H).
实施例16
Z-His-Asp-fmk
白色固体。1H NMR(CD3OD):8.78(s,1H),7.93(s,1H),7.36-7.33(m,7H),5.52(s,2H),5.10(s,2H),4.49(s,1H),3.13-3.05(m,2H),2.84(s,2H).
实施例17
Z-Tyr-Asp-fmk
如实施例3和4中所述,从Z-Tyr(Bu-t)-OH和3-氨基-5-氟-4-羟基戊酸叔丁酯制备Z-Tyr(Bu-t)-Asp-fmk叔丁酯。向Z-Tyr(Bu-t)-Asp-fmk叔丁酯(15mg,0.027mmol)的二氯甲烷溶液(1mL)中加入TFA(1mL)。该混合物在室温下搅拌8小时,然后在4℃下搅拌2天。用乙酸乙酯(30mL)将其稀释,用水(4×20mL)和盐水洗涤,用硫酸钠干燥并真空浓缩,得到黄色固体标题化合物(10mg,0.022mmol,83%)。1H NMR(DMSO-d6):δ9.20(s,1H),8.50
(brs,1H),7.50(m,1H),7.32-7.03(m,7H),6.63(d,J=7.5,2H),4.94(s,2H),
4.55(m,1H),4.15(m,1H),2.90-2.60(m,4H).
实施例18
Z-Val-Asp-fmk甲酯
向在冰浴中冷却的Z-Val-Asp-fmk(110mg,0.28mmol)的MeOH溶液(20mL)中缓慢通入HCl气流,直到用pH试纸测定该溶液已变为强酸性。该溶液在室温下搅拌4小时,然后蒸发。残余物用硅胶柱色谱法纯化(己烷-EtOAc,3∶2),得到63mg(55%)标题化合物,为白色固体。 1HNMR(CDCl3),0.91-0.87(m,6H),2.10-2.20(m,1H),2.81-2.88(m,1H),3.02-3.08(m,1H),3.675和3.682(2S,3H),3.97-4.01(m,1H),4.90-5.25(m,6H),6.94-7.02(m,1H),7.354(s,5H).
利用实施例18中描述的相同方法制得下列化合物。
实施例19
Z-Leu-Asp-fmk甲酯
无色粘性油。 1H NMR(CDCl3),0.92-0.94(m,6H),1.25-1.80
(m,4H),2.78-2.82(m,1H),3.00-3.05(m,1H),3.675(s,3H),4.15-4.20(m,
1H),4.85-5.10(m,6H),7.10-7.20(m,1H),7.344(s,5H).
实施例20
Z-Ile-Asp-fmk甲酯
白色固体。1H NMR(CDCl3),0.85-0.96(m,6H),1.14(m,1H),1.46
(s、1H),1.87(m,1H),1.91-2.86(m,1H),2.88-3.02(m,1H),3.257(s,3H),
4.68-4.06(m,1H),4.80-5.30(s,6H),6.99(m,1H),7.35(s,5H).
实施例21
用Hela细胞进行的细胞死亡试验
利用用肿瘤坏死因子-α(TNF-α)和环己酰亚胺(CHX)刺激的Hela细胞测试Cbz-Val-Asp(OMe)CH2F的细胞保护性能。这是编程性细胞死亡的一种已很好表征的细胞培养物模型,它通常用于分析抗编程性细胞死亡试剂。进行两种类型的实验:利用相差显微镜检查观察细胞而定性评估细胞死亡;和利用荧光染料钙黄绿素AM定量评估细胞死亡。
对于光显微镜检查,将Hela细胞以100000细胞/孔的密度接种到12孔板中的、含有2mM谷氨酰胺和10%胎牛血清的基本培养基中。24小时后,将该铺板培养基除去,加入含有不同浓度的细胞保护测试化合物的新鲜培养基。这些细胞在37℃下在CO2恒温箱中与测试化合物预培养2小时,然后加入TNF-α和CHX,使终浓度分别为25ng/mL和30μg/mL。培养24小时后,通过视觉检验这些细胞,以获得基于细胞形状和粘着度的细胞死亡的证据。如果细胞已变圆、相位明亮且已经与基层分离,就认为细胞已死亡。如果细胞仍保持它们的正常形状且与基层维持附着,就认为细胞仍活着。
对于定量试验来说,利用指示剂染料钙黄绿素AM定量分析在测试化合物存在下的细胞存活度。活细胞摄入该染料并将其转化为荧光衍生物;然后用荧光板读数器测定每孔中活化染料的量,用荧光度作为存活细胞数量的量度。为进行这些试验,将Hela细胞以25000细胞/孔的密度接种到48孔板中的、含有2mM谷氨酰胺和10%胎牛血清的0.4mL基本培养基中。24小时后,除去铺板培养基,加入含有不同浓度测试化合物的0.5mL新鲜培养基。这些细胞在37℃下在CO2恒温箱中与测试化合物预培养2小时,然后加入TNF-α和CHX,使终浓度分别为25ng/mL和30μg/mL。培养24小时后,将培养物用无血清、无酚红的Ham’s F12洗涤两次,以除去死亡细胞,并加入125μL含有8μM钙黄绿素AM的Ham’s F12。该培养物在室温下培养1小时,利用使用485nm(激发)和530nm(发射)过滤器装置的BioTek平板读数器测定荧光信号。数据以“相对对照百分数”表示,它用下列公式计算:将用CHX处理的培养物作为对照,而不是用未处理的培养物作为对照,以修正CHX的细胞抑制作用。不过,由于CHX自身也是Hela细胞的编程性细胞死亡的轻度诱导剂,强抗编程性细胞死亡药物将得到大于100%的相对对照百分数值。
典型的定性试验结果显示在图1A-1G,2A-2G和3A-3G中。在这些实验中,将Cbz-Val-Asp(OMe)-CH2F的细胞保护效能与BOC-Asp(OMe)-CH2F、Cbz-Glu(OMe)-Val-Asp(OMe)-CH2F、和Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F在三个不同浓度:0.5、5和50μM下进行对比。所有这些化合物均是甲酯衍生物。图1A-1G显示:在50μM浓度下,Cbz-Val-Asp(OMe)-CH2F(图1D)完全保护了Hela细胞免受TNF-α和CHX的编程性细胞死亡作用。在50μM时,相关肽BOC-Asp(OMe)-CH2F(图1C)和Cbz-Glu(OMe)-Val-Asp(OMe)-CH2F(图1E)也是保护剂。CPP32抑制剂Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F(图1F)在50μM时仅是勉强有效的细胞保护剂。图2A-2G显示,在5μM浓度下,Cbz-Val-Asp(OMe)-CH2F(图2D)仍令人惊奇地显示出强细胞保护作用,而5μM BOC-Asp(OMe)-CH2F(图2C)和5μM Cbz-Glu(OMe)-Val-Asp(OMe)-CH2F(图2E)的效果较差。CPP32抑制剂Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F(图2F)在5μM时没有细胞保护性能。图3A-3G显示,即使在0.5μM下,Cbz-Val-Asp(OMe)-CH2F(图3D)仍是有效的细胞保护剂,而其他化合物(图3C、3E和3F)只有轻微的或是没有细胞保护作用。这些实验证明,Cbz-Val-Asp(OMe)-CH2F可在比其他推测的抗编程性细胞死亡剂低10-100倍的浓度下保护Hela细胞不受TNF-α/CHX诱导的编程性细胞死亡。
如上所述,利用钙黄绿素AM进行的定量实验证实了用显微镜检验得到的结果。图4和5说明了两个这样的实验结果,其中将Cbz-Val-Asp(OMe)-CH2F(a)的细胞保护性能与BOC-Asp(OMe)-CH2F(b)(图5)和Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F(c)(图4)在三种浓度(0.5、5和50μM)下进行对比。图4显示,Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F(b)即使以最高浓度(50μM)使用,它在保护Hela细胞不受TNF-α/CHX伤害中也只有最小限度的功效。图5显示,50和5μM的BOC-Asp(OMe)-CH2F(b)是有效的细胞保护剂,但在0.5μM时,其活性显著降低。相比之下,0.5μM的Cbz-Val-Asp(OMe)-CH2F(a)作为细胞保护剂与50μM的Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F(b)功效相同(图4)。另外,0.5μM的Cbz-Val-Asp(OMe)-CH2F(a)是高活性的,而0.5μM的BOC-Asp(OMe)-CH2F(b)没有活性(图5)。
为了确定低剂量的Cbz-Val-Asp(OMe)-CH2F的效果,用0.05μM-1μM浓度范围内的该化合物处理Hela细胞。如图6所示,在低至0.25μM浓度时,Cbz-Val-Asp(OMe)-CH2F(a)产生了显著的保护作用。相比之下,在细胞死亡研究中广泛使用的抗编程性细胞死亡剂Cbz-Val-Ala-Asp(OMe)-CH2F(b)在此浓度范围内显示没有细胞保护作用。
合起来看,从图1A到图6说明的这些实验显示,Cbz-Val-Asp(OMe)-CH2F是完整细胞的令人惊奇的强抗编程性细胞死亡剂,它比其他任何已知的caspase抑制剂的作用都强。
实施例22
抑制Jurkat细胞中的PARP裂解
聚(ADP)核糖聚合酶(PARP)的裂解可能发生在其中caspase蛋白水解级联反应被激活的所有细胞中。出于这种原因,PARP裂解被广泛用作caspase介导的编程性细胞死亡的生化标记。细胞保护药物阻断PARP裂解的能力被认为是药物抑制caspase蛋白水解级联反应能力的象征,特别是抑制CPP32(caspase-3)这种主要的PARP蛋白酶的能力的象征。在一种人T细胞系-Jurkat细胞的Fas介导的编程性细胞死亡过程中检验Cbz-Val-Asp(OMe)-CH2F抑制PARP裂解的能力。这种编程性细胞死亡的细胞培养物模型的特性已被较好地描述,并且已知它与至少两种caspase(caspase-3(CPP32)和caspase-8(FLICE/MACH))的活化有关。
对于PARP裂解测定来说,将Jurkat细胞以500000细胞/孔的密度接种到六孔板中的含有10%FBS的RPMI1640培养基中。这些细胞在37℃下在CO2恒温箱中与Cbz-Val-Asp(OMe)-CH2F或其他测试化合物预培养2小时,然后加入Fas的单克隆抗体,使终浓度为500ng/mL。在37℃下在CO2恒温箱中继续再培养4小时。培养期结束时,通过离心收获这些细胞并在含有50mM Tris-HCl,pH7.4、150mM NaCl、1%NP-40、0.25%脱氧胆酸钠、1mM EDTA和蛋白酶抑制剂混合物的缓冲液中裂解。将相当于10-20μg蛋白质的适量裂解物加样到7.5%SDS聚丙烯酰胺凝胶上,在25mA下电泳2-2.5小时。然后将蛋白质转移到PVDF膜上,用PARP的兔多克隆抗体进行探测,并利用化学萤光法观察。
图7A-7E显示了三个这样的实验的结果。Jurkat细胞用0.5、5或50μM的下列化合物预培养:Cbz-Val-Asp(OMe)-CH2F(化合物1);BOC-Asp(OMe)-CH2F(化合物5);Cbz-Asp-α-([2,6-二氯苯甲酰氧基]-甲基酮(化合物6);Cbz-Glu(OMe)-Val-Asp(OMe)-CH2F(化合物3);Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F(化合物2);Cbz-Ile-Glu(OMe)-Thr-Asp(OMe)-CH2F(化合物4);或Cbz-Val-Ala-Asp(OMe)-CH2F(化合物7)。然后这些细胞用抗Fas处理并进行蛋白质印迹分析。Cbz-Val-Asp(OMe)-CH2F(化合物1)在50μM和5μM时完全抑制了PARP裂解,甚至在0.5μM时也显著抑制裂解(图7A)。相比之下,Cbz-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-CH2F(化合物2)(图7A)和Cbz-Ile-Glu(OMe)-Thr-Asp(OMe)-CH2F(化合物4)(图7C)以及Cbz-Asp-DCB(化合物6)(图7D)在50μM时完全抑制了PARP裂解,但在5μM和0.5μM时仅是勉强有效的抑制剂。BOC-Asp(OMe)-CH2F(化合物5)(图7D)和Cbz-Val-Ala-Asp(OMe)-CH2F(化合物7)(图7E)以及Cbz-Glu(OMe)-Val-Asp(OMe)-CH2F(化合物3)(图7B)在50μM和5μM时是PARP裂解的有效抑制剂,但在0.5μM时仅勉强有效,而在此浓度下,Cbz-Val-Asp(OMe)-CH2F(化合物1)仍显示出明显的抑制作用(图7A)。这些实验证明,Cbz-Val-Asp(OMe)-CH2F可在比其他已知caspase抑制剂低至少10倍的浓度下阻断完整细胞中的caspase蛋白水解级联反应。
实施例23
酶活性
用荧光酶试验测定Cbz-Val-Asp(OMe)-CH2F和Cbz-Val-Asp-CH2F(游离酸)作为CPP32、ICE和组织蛋白酶B的抑制剂的活性。通过利用杆状病毒作为载体,在昆虫宿主细胞(sf9细胞)中表达编码这些酶的DNA克隆,制备重组CPP32蛋白质和ICE蛋白质。参见Webb,N.R.等,“利用重组杆状病毒表达蛋白质”,工艺方法(Techniques)2:173-188(1990)。天然组织蛋白酶的制剂从商业来源获得。酶活性利用附着于荧光离去基的合成肽底物进行测定。酶对合成底物的裂解产生荧光信号,其用分光荧光计或用荧光微量滴定板读数器读数。
CPP32活性利用下列缓冲条件进行测量:100mM HEPES pH7.5,加有10%蔗糖,1%CHAPS,5mM谷胱甘肽和5μM肽底物。肽底物由具有序列Asp-Glu-Val-Asp的低聚物和与C末端缀合的荧光化合物氨基甲基香豆素组成。酶活性测定通常在37℃下进行30分钟。
表Ⅰ列出了Cbz-Val-Asp(OMe)-CH2F和Cbz-Val-Asp-CH2F(游离酸)对CPP32和其他蛋白酶的IC50。
表Ⅰ:Cbz-Val-Asp(OMe)-CH2F和Cbz-Val-Asp-CH2F(游离酸)
作为CPP32和其他蛋白酶的抑制剂的效能
酶 Cbz-Val-Asp(OMe)-CH2F Cbz-Val-Asp-CH2F(游离酸)
IC50(μM) IC50(μM)
CPP32 1.1 0.043
ICE 0.9 0.02
组织蛋白酶B 0.3 >10
Xa因子 >100 >100
凝血酶 >100 >100
表Ⅰ中显示的结果表明,本发明化合物是CPP32和ICE的中等强度的抑制剂。结果还表明,Cbz-Val-Asp-CH2F是CPP32和ICE的强抑制剂和选择性抑制剂。
Cbz-Val-Asp-CH2F对从PharMington(Becton分公司,SanDiego,CA)得到的重组caspase 3、6、7和8的抑制活性利用Ac-DEVD-AMC测定。每个试验中的每种酶的用量如下:1ng caspase3,15ng caspase6,2ng caspase7和60ng caspase8。酶反应在96孔板中利用caspase缓冲液(20mM PIPES,100mM NaCl,10mM DTT,1mM EDTA,0.1%CHAPS和10%蔗糖,pH7.2)进行,该反应通过加入10μM Ac-DEVD-AMC(购自Quality Controlled Biochemicals,Inc.Hopkinton,MA)引发。从30pM到10μM的12种浓度的Cbz-Val-Asp-CH2F化合物在与重组caspase于37℃下孵育30分钟后进行测试。用采用355nm激发过滤器/460nm发射过滤器的荧光板读数器(EC&G WALLAG,1420-002型)对该板读数。数据利用GraphPrism软件进行分析。数据总结于表Ⅱ中。
表Ⅱ:Cbz-Val-Asp-CH2F作为caspase抑制剂的效能
Caspase-3 | Caspase-6 | Caspase-7 | Caspase-8 | |
IC50(nM) | 19.8 | 18.4 | 6.8 | 7.2 |
表Ⅱ中显示的结果表明,Cbz-Val-Asp-CH2F是所有被测试caspase的强抑制剂。
表Ⅲ显示了各种二肽抑制剂对caspase-3的活性。结果表明,在所测试的化合物中,Z-Val-Asp-CH2F是最强的caspase-3抑制剂。
表Ⅲ.二肽抑制剂的Caspase-3活性
名称 | Caspase-3 IC50(μM) |
Z-L-Val-Asp-fmk | 0.04 |
Z-L-Leu-Asp-fmk | 0.2 |
Z-L-Ile-Asp-fmk | 0.7 |
Z-L-Phe-Asp-fmk | 0.4 |
Z-Gly-Asp-fmk | 1.9 |
Z-L-Ala-Asp-fmk | 0.6 |
Z-β-Ala-Asp-fmk | 3.5 |
Ac-L-Val-Asp-fmk | 0.25 |
Z-L-Glu-Asp-fmk | 14.2 |
Z-L-Lys-Asp-fmk.TFA | 1.6 |
Z-N-Me-L-Val-Asp-fmk | 1.3 |
Z-L-Pro-Asp-fmk | 0.41 |
Z-L-His-Asp-fmk | 0.77 |
Z-L-Tyr-Asp-fmk | 0.66 |
实施例24
Z-VD-fmk对PARP裂解的作用
聚(ADP)核糖聚合酶(PARP)是首先确定的caspase-3底物之一,PARP的裂解仍被认为是caspase-3活化和caspase介导的编程性细胞死亡的近似通用标记。因此,抗编程性细胞死亡化合物阻断PARP裂解的能力是其抑制编程性细胞死亡能力的有用的指示。利用抗Fas处理的Jurkat细胞来检验Z-VD-fmk在PARP裂解试验中的效能。将2×106Jurkat细胞接种到6孔皿的每一个孔中,并用测试化合物预培养30分钟。然后这些细胞用500ng/mL兴奋性抗Fas抗体或PBS刺激4小时。之后收获这些细胞,轻柔地使它们成团,用PBS洗涤两次,并使其在RIPA缓冲液中裂解。等分的裂解液用SDS-PAGE进行分析,将蛋白质转移到PVDF膜上进行蛋白质印迹分析。一抗是与全长PARP和caspase-3生成的裂解产物均有交叉反应的多克隆抗PARP血清。
图8A显示,Z-VD-fmk在500和250nM浓度时完全抑制了PARP裂解(注意没有85KDa带)。Z-VD-fmk的浓度即使低至50nM时仍保持了其大部分抑制活性(图8A)。相比之下,尽管Z-VAD-fmk在5μM浓度时是PARP裂解的有效抑制剂(数据未显示),但其效率在500nM时要小得多(图8B)。这些实验显示,Z-VD-fmk作为完整细胞中PARP裂解抑制剂的效能比Z-VAD-fmk高至少10倍,在这种完整细胞编程性细胞死亡模型中,Z-VD-fmk的IC50值小于50nM。
实施例25
Z-VD-fmk对TNF-α诱导的细胞死亡的作用
肿瘤坏死因子-α(TNF-α)可以在大量细胞类型中通过启动caspase级联反应而引发编程性细胞死亡,其编程性细胞死亡诱导活性可以被肽基caspase抑制剂抑制。不过,要产生良好的抗编程性细胞死亡作用,必需要高浓度的抑制剂(50μM或更高)。这里用TNF-α细胞死亡研究中常用的细胞系-Hela细胞来确定Z-VD-fmk的抗编程性细胞死亡效能。
在处理前24小时,将Hela细胞以50000细胞/孔的密度接种到48孔板中。然后将它们用不同浓度的Z-VD-fmk预培养2小时,并用TNF-α(25ng/mL)和环己酰亚胺(CHX;30μg/mL)进行刺激。将该培养物再培养24小时,用PBS洗涤两次除去死亡细胞。每份培养物再用钙黄绿素AM(钙黄绿素AM是一种前荧光染料,它被活细胞摄入并转化为荧光产物)培养45分钟,由此测量存活细胞的密度。所得数据用“%相对对照”值表示(对照值是与环己酰亚胺、但无TNF-α一起温育的细胞得到的值)。
图9显示了从0到500nM测试浓度范围内的Z-VD-fmk的结果。Z-VD-fmk在浓度接近100nM时产生了良好的细胞保护作用。相比之下,Z-VAD-fmk在低于1μM时失去了其大部分细胞保护性能(数据未显示)。四肽抑制剂,诸如Z-DEVD-fmk和Ac-DEVD-CHO,在低于50μM时效率非常低(数据未显示)。因此,Z-VD-fmk不仅在亚微摩尔浓度水平抑制PARP裂解(参见实施例24),而且在亚微摩尔浓度水平抑制细胞死亡,它比已知的三肽和四肽抑制剂有效得多。
实施例26
Z-VD-fmk对DNA梯状化的作用
在编程性细胞死亡的后期,随着细胞质碎片脱散(通过起泡)和核分解,细胞开始完全崩溃。核分解的证据之一是基因组DNA裂解成核小体大小的片段(叫做“DNA梯状化”)。DNA梯状化象其他后期编程性细胞死亡事件一样,被认为是不可逆的,因此确定抗编程性细胞死亡药物是否能预防其发生是很重要的。
Z-VD-fmk阻断DNA梯状化的能力利用抗Fas处理的Jurkat细胞进行检验。将Jurkat细胞以5×106细胞的密度铺板到60mm培养皿中,并用不同浓度的Z-VD-fmk预培养。然后它们用100ng/mL的抗Fas刺激4小时,将它们收获,使之成团并用PBS洗涤两次。基因组DNA利用Eldadah等(1996)的方法进行分离。简单地说,将细胞溶解于2mL 7M盐酸胍中并与1mL Wizard小量制备DNA纯化树脂(Promega)混合。该树脂/DNA复合物用缓冲液洗涤两次,DNA用TE洗脱。将1-2μg的该DNA样品在1%琼脂糖/TBE凝胶上电泳,该凝胶用溴化乙锭染色。
图10显示了DNA梯状化试验的结果,其中细胞用Z-VD-fmk或药物载体(DMSO)预培养。用抗Fas刺激的载体处理细胞显示了DNA的特征性梯状化模式,它向下扩展到约300bp。相比之下,Z-VD-fmk的剂量低至50nM时抑制了梯状化形成。
这一结果显示,Z-VD-fmk可在相当于阻断细胞死亡和PARP裂解的浓度的亚微摩尔浓度下阻断危险的后期编程性细胞死亡(DNA梯状化)。基于此实验和实施例24和25中描述的数据可以得出结论:Z-VAD-fmk是编程性细胞死亡的完整细胞模型的高效、亚微摩尔编程性细胞死亡抑制剂。
实施例27
Cbz-Val-Asp-CH2F在小鼠肝编程性细胞死亡模型中的
抗编程性细胞死亡活性
该研究中使用3-4周龄的雌性小鼠。通过静脉注射2-6μg抗小鼠Fas抗原的纯化仓鼠抗小鼠Fas单克隆抗体(克隆Jo2,Pharmingen),该抗体用80μl磷酸盐缓冲的生理盐水稀释,使这些小鼠的肝脏变性(Rodriguez等,1996)。用死亡率作为评估肝脏变性的终点。Cbz-Val-Asp-CH2F用Tris缓冲液配制用于静脉滴注,并经尾静脉以1-10mg/kg的剂量静脉注射给药。10分钟后,给动物注射Fas抗体。在30分钟、1、3和24小时时对死亡率计数。对于每种化合物都有只接受Fas抗体的对照动物组。对接受最高剂量的那些动物观察它们的急性行为反映(例如,镇静、运动活跃性、步态改变、惊厥、straub tail、震颤等),然后将它们关笼过夜并在第二天检查毒性/死亡率。
在这些实验中,Cbz-Val-Asp-CH2F是抗Fas诱导的致死率的令人惊奇的强抑制剂。静脉注射单一的1mg/kg剂量就在抗体给药后不超过1小时完全保护了小鼠免受抗Fas的伤害,剂量低至0.25mg/kg仍产生了近乎100%的保护作用。相比之下,在载体对照组中,所有的小鼠在这一时间点时都死了。Cbz-Val-Asp-CH2F还显示了不超过24小时的实质性保护作用(28%存活)。独立的研究显示,对致死率的保护与肝酶SPGT和SGOT的诱导作用的预计减弱有关。
这些结果证明,Cbz-Val-Asp-CH2F在对小鼠肝编程性细胞死亡模型系统给药后在体内是高活性的。
实施例28
Cbz-Val-Asp-CH2F在病灶局部缺血的大鼠模型中的
神经保护作用
(ⅰ)准备性手术:使用重200-240g的雄性Fischer-344大鼠(Harlan Sprague Dawley,CA)。这些动物首先在30%氧和70%空气的混合物中用3%氟烷麻醉。将氟烷浓度减小到1.5%用于维持整个手术过程中的麻醉状态。准备性手术包括:(a)静脉导管植入:暴露左股静脉,插入填充有载体的Teleflex导管直到下腔静脉,用于随后的给药。(b)动脉导管植入:在股动脉插套管,用于在局部缺血过程中、开始给药时和动脉再灌注时,监测血压以及其他生理条件包括pO2、pCO2、pH、葡萄糖、血细胞比容。动脉和静脉导管都通过动物的背部外置,以便能自由移动。(c)将PhysioTel传递器(Data Sciences International,MI)植入腹腔,以远程监测动物22小时的体温。
(ⅱ)生理学参数:在手术过程中,利用YSI可再用温度探针(YSI有限公司,Yellow Spring,OH)使核心体温维持37.5℃,所述探针与YSI温度控制装置(73A型,YSI有限公司,Ohio)和电热垫(756型,Sunbean-Oster有限公司,Hattiesburg,MS)连接。局部缺血后,PhysioTel传递器被激活,每5分钟记录核心体温。整个手术中,在药物(药团)静脉滴注过程中和局部缺血开始后1、2、3和4小时,监测系统血压。在动脉闭塞和再灌注时,测定其他生理学条件,包括pO2、pCO2、pH、葡萄糖和血细胞比容。
(ⅲ)瞬时病灶局部缺血模型:准备性手术后,沿腹侧中线进行颈切口,以暴露出两个CCA。右CCA用4-0号结扎丝线永久结扎,而左CCA用无创伤动脉瘤夹夹紧。垂直于右眼的旁侧眼角和外耳道之间一条线并与其交叉地作一个1cm的切口。切开下面的颞肌并牵开,并使之在解剖显微镜(SZ-STB1型,Olympus,日本)的帮助下直接观察,大脑中动脉(MCA)通过一个2mm钻孔暴露,该孔向颧弓和颞鳞骨的融合处钻入2-3mm。钻孔在用生理盐水连续冲洗的条件下进行。切割并拉开硬脑膜以暴露出鼻裂中的MCA。因MCA流过鼻裂,故用科德曼微动脉瘤夹(1号)暂时闭合MCA。用解剖显微镜检验血流的中断。用外科手术夹封闭切口,终止麻醉,动物苏醒后(几分钟内)将它们返回到自己的笼中。经受瞬时局部缺血的大鼠在MCA闭合后2.5小时后再次麻醉。确认MCA闭合后,将MCA和左CCA上的夹子除去,视觉观察证实MCA中血流恢复。将切口封闭,大鼠返回到自己的笼中。让需要短期复原的动物存活24小时。所有动物在处死前深度麻醉。将大脑取出,作2mm冠状面的切片并置于TTC中。梗塞组织看起来苍白,可以与相邻的活组织区别开。皮质和皮质下的梗塞面积用图像加工软件盲测,梗塞体积通过将已知厚度的各测量值合计计算出来。
(ⅳ)统计分析:对实验组和对照组中的每一个动物小组的所有生理学参数、温度记录和皮质梗塞体积进行统计学对比。统计学分析利用Sigmastat软件(Jandel Scientific Software,SanRafael,CA)进行。未成对数据进行T检验,ANOVA用于多重比较。p值小于0.05被认为是显著的。用SigmaPlot v2.01软件(JandelScientific)绘制曲线图。
在两个中风研究实验中,用大鼠(Fischer-344)瞬时病灶局部缺血模型检验Cbz-Val-Asp-CH2F的体内神经保护性能。局部缺血发生后10分钟,静脉输注20mg/kg Cbz-Val-Asp-CH2F,接着连续静脉滴注5mg/kg/h。在实验1中,连续滴注6小时。在实验2中,滴注延长至12小时。
在两个研究中均发现Cbz-Val-Asp-CH2F显著减少了皮质梗塞:实验1中为46%(p<0.05),实验2中为57%(p<0.05)(图11A和11B)。给药后,血压、血内气体、或温度都没有变化。这些结果证明,Cbz-Val-Asp-CH2F在紧急静脉内给药后是良好耐受的,并且它是瞬时病灶脑局部缺血的大鼠模型的强神经保护剂。
现在已对本发明进行了全面描述,本领域普通技术人员将能明了,本发明可在不影响本发明范围或其任何实施方案的广泛而等价的疾病、制剂和其他参数内完成。本文中提及的所有专利和出版物均全文引入作为参考。
Claims (32)
2、如权利要求1所述的化合物,其中R1是叔丁氧基羰基、乙酰基或苯甲氧基羰基。
3、如权利要求1所述的化合物,其中AA是Gly,Thr,Glu,Lys,Arg,Ser,Asn,Gln,Val,Ala,Leu,Ile,Met,或β-Ala。
4、如权利要求1所述的化合物,其中R2是H或CH2F。
5、如权利要求1所述的化合物,其中R3是H或C1-6烷基。
7、如权利要求1所述的化合物,其中所述化合物选自:
Boc-Ala-Asp-CH2F,
Boc-Val-Asp-CH2F,
Boc-Leu-Asp-CH2F,
Ac-Val-Asp-CH2F,
Ac-Ile-Asp-CH2F,
Ac-Met-Asp-CH2F,
Cbz-Val-Asp-CH2F,
Cbz-β-Ala-Asp-CH2F,
Cbz-Leu-Asp-CH2F,
Cbz-Ile-Asp-CH2F,
Boc-Ala-Asp(OMe)-CH2F,
Boc-Val-Asp(OMe)-CH2F,
Boc-Leu-Asp(OMe)-CH2F,
Ac-Val-Asp(OMe)-CH2F,
Ac-Ile-Asp(OMe)-CH2F,
Ac-Met-Asp(OMe)-CH2F,
Cbz-Val-Asp(OMe)-CH2F,
Cbz-β-Ala-Asp(OMe)-CH2F,
Cbz-Leu-Asp(OMe)-CH2F,和
Cbz-Ile-Asp(OMe)-CH2F
8、如权利要求1所述的化合物,其中所述化合物选自:
Cbz-Val-Asp-CH2F,和
Cbz-Val-Asp(OMe)-CH2F。
9、一种药物组合物,它包含权利要求1的化合物和药学上可接受的载体。
10、一种抑制细胞或组织内细胞死亡的方法,它包含使所述细胞或组织与有效量的权利要求1化合物接触。
11、一种治疗或改善动物的中枢和周围神经系统、视网膜神经元、心肌或免疫系统细胞中的细胞死亡的方法,它包含给予需要这种治疗或改善的动物有效量的权利要求1化合物。
12、如权利要求11所述的方法,其中所述细胞死亡是在中枢或周围神经系统中,并且是由于下列原因之一引起的:
(a)选自因中风导致的病灶局部缺血和因心搏停止导致的普遍缺血的缺血和兴奋毒性疾病;
(b)创伤性损伤;
(c)病毒感染;
(d)辐射诱导的神经细胞死亡;或
(e)选自早老性痴呆、帕金森氏症、朊病毒疾病、多发性硬化、肌萎缩性侧索硬化和脊髓延髓萎缩的神经变性疾病。
13、如权利要求11所述的方法,其中所述细胞死亡是在中枢或周围神经系统中,并且是由于特异基因的三核苷酸重复区的扩展引起的。
14、如权利要求11所述的方法,其中所述细胞死亡是由于杭廷顿氏舞蹈病引起的。
15、如权利要求11所述的方法,其中所述细胞死亡是在心肌组织中,并且是由于心肌梗塞、充血性心力衰竭、心肌病或心脏的病毒感染引起的。
16、如权利要求11所述的方法,其中所述细胞死亡是在视网膜神经元中,并且是由于眼内压升高、年龄相关性黄斑变性或色素性视网膜炎引起的。
17、如权利要求11所述的方法,其中所述细胞死亡是在免疫系统中,并且是由于选自获得性免疫缺陷综合征、重症联合免疫缺陷综合征和辐射诱导的免疫抑制的免疫缺陷疾病引起的。
18、如权利要求11所述的方法,其中所述细胞死亡是由于选自红斑狼疮、类风湿性关节炎和Ⅰ型糖尿病的自身免疫疾病引起的。
19、如权利要求11所述的方法,其中所述细胞死亡是由于Ⅰ型糖尿病引起的。
20、一种治疗或预防动物的多囊肾病或贫血/红细胞生成的方法,它包含给予需要这种治疗或预防的动物有效量的权利要求1化合物。
21、一种保护哺乳动物的器官或组织免受因正常血液供给丧失而导致的细胞死亡的方法,该方法包含将所述器官或组织与有效量的权利要求1化合物接触。
22、如权利要求21所述的方法,其中所述器官或组织在移植到哺乳动物体内之前存在于储存介质中。
23、如权利要求21所述的方法,其中所述接触包括将所述化合物注入到器官或组织中,或者将所述器官或组织浸浴在含有所述化合物的储存介质中。
24、一种减少或预防供体器官或组织在移植到宿主中后因宿主免疫细胞的作用而导致的细胞死亡的方法,该方法包含给予有这种需要的所述宿主有效量的权利要求1化合物。
25、一种减少或预防体外授精过程中所用的哺乳动物精子或卵细胞死亡的方法,包含将所述精子或卵细胞与有效量的权利要求1化合物接触。
26、一种延长哺乳动物或酵母细胞系的有效期限的方法,包含将所述细胞系与权利要求1化合物接触。
27、如权利要求26所述的方法,其中所述接触包括在细胞培养基中含有所述化合物。
28、一种治疗或改善哺乳动物毛发损失或毛发过早斑白的方法,包含将有这种需要的哺乳动物毛发或毛囊与权利要求1化合物接触。
29、如权利要求28所述的方法,其中治疗的是毛发损失,且所述毛发损失是由于男性模式秃发、辐射、化疗或情绪压力引起的。
30、一种治疗或改善哺乳动物因接触高水平辐射、热或化学物质而引起的皮肤损伤的方法,该方法包含在有这种需要的哺乳动物皮肤上施用权利要求1化合物。
31、如权利要求30所述的方法,其中所述化合物作为油膏的一部分应用。
32、如权利要求30所述的方法,其中所述皮肤损伤是由于严重阳光照射过度引起的,并且其中所述治疗减少了皮肤起疱和脱皮。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US6167697P | 1997-10-10 | 1997-10-10 | |
US60/061,676 | 1997-10-10 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1301131A true CN1301131A (zh) | 2001-06-27 |
CN1138472C CN1138472C (zh) | 2004-02-18 |
Family
ID=22037372
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB988100223A Expired - Fee Related CN1138472C (zh) | 1997-10-10 | 1998-10-09 | 二肽型编程性细胞死亡抑制剂及其用途 |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP1033910A4 (zh) |
JP (1) | JP4439111B2 (zh) |
KR (1) | KR100580333B1 (zh) |
CN (1) | CN1138472C (zh) |
AU (1) | AU741203B2 (zh) |
BR (1) | BR9814817A (zh) |
CA (1) | CA2306692C (zh) |
EA (1) | EA200000409A1 (zh) |
NO (1) | NO20001323L (zh) |
WO (1) | WO1999018781A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023213293A1 (zh) * | 2022-05-06 | 2023-11-09 | 北京康蒂尼药业股份有限公司 | 一种二肽衍生物组合物及其制备方法和用途 |
Families Citing this family (32)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6184210B1 (en) | 1997-10-10 | 2001-02-06 | Cytovia, Inc. | Dipeptide apoptosis inhibitors and the use thereof |
ATE295177T1 (de) * | 1998-03-16 | 2005-05-15 | Cytovia Inc | Dipeptid kaspase inhibitoren und deren verwendung |
WO1999062554A1 (fr) | 1998-05-29 | 1999-12-09 | Mochida Pharmaceutical Co., Ltd. | Preparations de prevention / de traitement de maladies demyelinisantes auto-immunes |
AU773891C (en) | 1998-10-23 | 2005-02-17 | Kirin-Amgen Inc. | Dimeric thrombopoietin peptide mimetics binding to MP1 receptor and having thrombopoietic activity |
US7488590B2 (en) | 1998-10-23 | 2009-02-10 | Amgen Inc. | Modified peptides as therapeutic agents |
US6660843B1 (en) | 1998-10-23 | 2003-12-09 | Amgen Inc. | Modified peptides as therapeutic agents |
WO2000044216A2 (en) | 1999-02-01 | 2000-08-03 | Cytovia Inc | Gambogic acid, analogs and derivatives as activators of caspases and inducers of apoptosis |
EP1165490B1 (en) | 1999-03-16 | 2006-08-16 | Cytovia, Inc. | Substituted 2-aminobenzamide caspase inhibitors and the use thereof |
ATE363465T1 (de) | 1999-04-09 | 2007-06-15 | Cytovia Inc | Caspase inhibitoren und ihre verwendung |
EA200200301A1 (ru) | 1999-08-27 | 2002-08-29 | Сайтовиэ, Инк. | ЗАМЕЩЕННЫЕ α-ГИДРОКСИКИСЛОТЫ, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СПОСОБ ИНГИБИРОВАНИЯ КЛЕТОЧНОЙ ГИБЕЛИ НА КЛЕТОЧНОМ ИЛИ ТКАНЕВОМ УРОВНЕ, СПОСОБ ЛЕЧЕНИЯ ИЛИ ОБЛЕГЧЕНИЯ СОСТОЯНИЯ ПРИ ГИБЕЛИ КЛЕТОК У ЖИВОТНОГО, СПОСОБ ЛЕЧЕНИЯ ИЛИ ПРОФИЛАКТИКИ РАЗЛИЧНЫХ БОЛЕЗНЕЙ |
US6566338B1 (en) | 1999-10-12 | 2003-05-20 | Cytovia, Inc. | Caspase inhibitors for the treatment and prevention of chemotherapy and radiation therapy induced cell death |
US6303374B1 (en) | 2000-01-18 | 2001-10-16 | Isis Pharmaceuticals Inc. | Antisense modulation of caspase 3 expression |
DE10006889A1 (de) * | 2000-02-16 | 2001-09-06 | Procorde Gmbh | Verwendung von Inhibitoren von Caspase-3 oder der Caspase-aktivierten Desoxyribonuclease (CAD) zur Behandlung von Herzerkrankungen |
CN1994298A (zh) * | 2000-03-29 | 2007-07-11 | 沃泰克斯药物股份有限公司 | 氨基甲酸酯天冬氨酸特异性半胱氨酸蛋白酶抑制剂及其用途 |
SI1268425T1 (sl) | 2000-03-29 | 2008-04-30 | Vertex Pharma | Zaviralci karbamat kaspaze in uporaba le-teh |
AU2001265008A1 (en) * | 2000-05-23 | 2001-12-03 | Vertex Pharmaceuticals Incorporated | Caspase inhibitors and uses thereof |
US20020052323A1 (en) * | 2000-08-30 | 2002-05-02 | Jinhai Wang | Quinoline-(C=O)-(multiple amino acids)-leaving group compounds for pharmaceutical compositions and reagents |
US6800619B2 (en) | 2000-09-13 | 2004-10-05 | Vertex Pharmaceuticals Incorporated | Caspase inhibitors and uses thereof |
HUP0302173A2 (hu) | 2000-09-15 | 2003-09-29 | Vertex Pharmaceuticals Incorporated | Protein kináz inhibitorokként alkalmazható pirazolvegyületek |
US6660731B2 (en) | 2000-09-15 | 2003-12-09 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
ES2265452T3 (es) | 2000-12-21 | 2007-02-16 | Vertex Pharmaceuticals Incorporated | Compuestos de pirazol utiles como inhibidores de la proteina quinasa. |
MXPA03009647A (es) | 2001-04-19 | 2004-01-29 | Vertex Pharma | Heterociclildicarbamidas como inhibidores de caspasa. |
MY141867A (en) | 2002-06-20 | 2010-07-16 | Vertex Pharma | Substituted pyrimidines useful as protein kinase inhibitors |
WO2004013140A1 (en) | 2002-08-02 | 2004-02-12 | Vertex Pharmaceuticals Incorporated | Pyrazole compositions useful as inhibitors of gsk-3 |
CA2501196A1 (en) * | 2002-10-10 | 2004-04-22 | Becton, Dickinson And Company | Sample collection system with caspase inhibitor |
US8008453B2 (en) | 2005-08-12 | 2011-08-30 | Amgen Inc. | Modified Fc molecules |
AR056763A1 (es) | 2005-11-03 | 2007-10-24 | Vertex Pharma | Aminopirimidinas sustituidas con tiazol o pirazol,utiles como agentes anticancer y composiciones farmaceuticas que las contienen. |
CA2685876A1 (en) | 2007-05-02 | 2008-11-13 | Vertex Pharmaceuticals Incorporated | Thiazoles and pyrazoles useful as kinase inhibitors |
WO2009018415A1 (en) | 2007-07-31 | 2009-02-05 | Vertex Pharmaceuticals Incorporated | Process for preparing 5-fluoro-1h-pyrazolo [3, 4-b] pyridin-3-amine and derivatives thereof |
FR2923160B1 (fr) * | 2007-11-02 | 2013-07-26 | Pasteur Institut | Composes destines a prevenir ou traiter une infection virale. |
EP2323622A1 (en) | 2008-09-03 | 2011-05-25 | Vertex Pharmaceuticals Incorporated | Co-crystals and pharmaceutical formulations comprising the same |
CN106317161B (zh) * | 2015-06-29 | 2020-05-15 | 深圳翰宇药业股份有限公司 | 一种氟甲基酮肽系列化合物的制备方法 |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1991015577A1 (en) * | 1990-04-04 | 1991-10-17 | Black, Roy, A. | INTERLEUKIN 1'beta' PROTEASE |
EP0519748B1 (en) * | 1991-06-21 | 1998-09-02 | Merck & Co. Inc. | Peptidyl derivatives as inhibitors of interleukin-1B converting enzyme |
AU657701B2 (en) * | 1991-08-30 | 1995-03-23 | Vertex Pharmaceuticals Incorporated | Interleukin 1beta protease and interleukin 1beta protease inhibitors |
US5462939A (en) * | 1993-05-07 | 1995-10-31 | Sterling Winthrop Inc. | Peptidic ketones as interleukin-1β-converting enzyme inhibitors |
JPH0789951A (ja) * | 1993-06-03 | 1995-04-04 | Sterling Winthrop Inc | インターロイキン−1β転換酵素阻害剤 |
US5565430A (en) * | 1994-08-02 | 1996-10-15 | Sterling Winthrop Inc. | Azaaspartic acid analogs as interleukin-1β converting enzyme inhibitors |
ATE310528T1 (de) * | 1996-09-12 | 2005-12-15 | Idun Pharmaceuticals Inc | Hemmung der apoptose unter verwendung von inhibitoren der interleukin-1 beta converting enzym (ice)/ced-3 familie |
-
1998
- 1998-10-09 BR BR9814817-6A patent/BR9814817A/pt not_active IP Right Cessation
- 1998-10-09 EP EP98952166A patent/EP1033910A4/en not_active Withdrawn
- 1998-10-09 CA CA2306692A patent/CA2306692C/en not_active Expired - Fee Related
- 1998-10-09 EA EA200000409A patent/EA200000409A1/ru unknown
- 1998-10-09 JP JP2000515426A patent/JP4439111B2/ja not_active Expired - Fee Related
- 1998-10-09 KR KR1020007003882A patent/KR100580333B1/ko not_active IP Right Cessation
- 1998-10-09 AU AU97930/98A patent/AU741203B2/en not_active Ceased
- 1998-10-09 WO PCT/US1998/021232 patent/WO1999018781A1/en active IP Right Grant
- 1998-10-09 CN CNB988100223A patent/CN1138472C/zh not_active Expired - Fee Related
-
2000
- 2000-03-14 NO NO20001323A patent/NO20001323L/no not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023213293A1 (zh) * | 2022-05-06 | 2023-11-09 | 北京康蒂尼药业股份有限公司 | 一种二肽衍生物组合物及其制备方法和用途 |
Also Published As
Publication number | Publication date |
---|---|
AU741203B2 (en) | 2001-11-22 |
EP1033910A4 (en) | 2004-11-24 |
CA2306692C (en) | 2010-09-21 |
KR100580333B1 (ko) | 2006-05-16 |
CA2306692A1 (en) | 1999-04-22 |
NO20001323D0 (no) | 2000-03-14 |
JP2001519358A (ja) | 2001-10-23 |
AU9793098A (en) | 1999-05-03 |
EP1033910A1 (en) | 2000-09-13 |
EA200000409A1 (ru) | 2000-10-30 |
KR20010031053A (ko) | 2001-04-16 |
NO20001323L (no) | 2000-06-13 |
CN1138472C (zh) | 2004-02-18 |
WO1999018781A1 (en) | 1999-04-22 |
BR9814817A (pt) | 2002-01-08 |
JP4439111B2 (ja) | 2010-03-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1138472C (zh) | 二肽型编程性细胞死亡抑制剂及其用途 | |
CN1297354A (zh) | 二肽卡斯帕酶抑制剂及其用途 | |
US6184210B1 (en) | Dipeptide apoptosis inhibitors and the use thereof | |
KR102362277B1 (ko) | 면역조절제로서 1,2,4-옥사디아졸 유도체 | |
CN1346344A (zh) | 取代的2-氨基苯甲酰胺天冬氨酸特异性半胱氨酸蛋白酶抑制剂及其应用 | |
CN1235875C (zh) | 取代的α-羟基酸天冬氨酸特异性半胱氨酸蛋白酶抑制剂及其用途 | |
DE60014345T2 (de) | Makrozyklische peptide als hepatitis c virus ns3 protease inhibitore | |
CN1127511C (zh) | 白介素-1β转化酶的抑制剂 | |
CN1349496A (zh) | Caspase抑制剂及其应用 | |
IE904555A1 (en) | HIV Protease inhibitors useful for the treatment of AIDS | |
KR20160081898A (ko) | 면역조절제로서 1,3,4-옥사디아졸 및 1,3,4-티아디아졸 유도체 | |
CN1377268A (zh) | 细胞粘合抑制剂 | |
CN1441785A (zh) | 可用作生长激素促分泌素的四氢异喹啉类似物 | |
KR20160075506A (ko) | 면역조절제로서 사이클릭 펩티도미메틱 화합물 | |
JPH02209854A (ja) | Aidsの治療に有用なhivプロテアーゼ阻害剤 | |
US9849112B2 (en) | Pyrrole compounds as Granzyme B inhibitors | |
CN1145637C (zh) | 作为金属蛋白酶和tnf释放抑制剂的硫取代的肽 | |
US9969770B2 (en) | Proline compounds as Granzyme B inhibitors | |
CN1653125A (zh) | 白内障和其它眼病发展的改善 | |
CA2908315A1 (en) | Cosmetic uses and methods for indoline granzyme b inhibitor compositions | |
CA2994181A1 (en) | Azaindoline compounds as granzyme b inhibitors | |
CN1486298A (zh) | 兴奋性氨基酸前体药物 | |
CN1285356A (zh) | 二肽化合物、其药用盐或酯、以其为活性成分的药物组合物及其治疗和预防细胞凋亡的应用 | |
MXPA00003260A (en) | Dipeptide apoptosis inhibitors and the use thereof | |
JP2002516337A (ja) | ガン、関節炎および網膜症を処置するための抗血管形成薬 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20040218 Termination date: 20131009 |