CA2616150A1

CA2616150A1 - Inhibition of the renin-angiotensin system for the treatment of renal, vascular and cartilage pathology

Inhibition of the renin-angiotensin system for the treatment of renal, vascular and cartilage pathology Download PDF

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Publication number: CA2616150A1
Authority: CA; Canada
Prior art keywords: disease; subject; gags; condition; regulating
Prior art date: 2005-07-27
Legal status : Abandoned

Application number

CA002616150A

Other languages

English (en)

French (fr)

Inventor

Talia Weinstein

Uzi Gafter

Zvi Nevo

Dror Robinson

Zoharia Evron

Current Assignee

Mor Research Applications Ltd

Original Assignee

Individual

Priority date

2005-07-27

Filing date

2006-07-27

Publication date

2007-02-01

2006-07-27 Application filed by Individual filed Critical Individual

2007-02-01 Publication of CA2616150A1 publication Critical patent/CA2616150A1/en

Status Abandoned legal-status Critical Current

Links

230000036454 renin-angiotensin system Effects 0.000 title claims abstract description 30
238000011282 treatment Methods 0.000 title claims description 34
210000000845 cartilage Anatomy 0.000 title claims description 23
230000005764 inhibitory process Effects 0.000 title description 9
230000007170 pathology Effects 0.000 title description 3
230000002792 vascular Effects 0.000 title description 3
238000000034 method Methods 0.000 claims abstract description 124
229920002683 Glycosaminoglycan Polymers 0.000 claims abstract description 121
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 102
201000010099 disease Diseases 0.000 claims abstract description 82
230000002222 downregulating effect Effects 0.000 claims abstract description 36
230000014509 gene expression Effects 0.000 claims abstract description 33
230000009286 beneficial effect Effects 0.000 claims abstract description 30
201000008482 osteoarthritis Diseases 0.000 claims abstract description 27
208000017520 skin disease Diseases 0.000 claims abstract description 21
239000003795 chemical substances by application Substances 0.000 claims description 79
-1 FR-900456 Chemical compound 0.000 claims description 65
239000005541 ACE inhibitor Substances 0.000 claims description 38
229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 38
108091034117 Oligonucleotide Proteins 0.000 claims description 34
230000000694 effects Effects 0.000 claims description 28
208000015100 cartilage disease Diseases 0.000 claims description 22
239000002333 angiotensin II receptor antagonist Substances 0.000 claims description 21
108010061435 Enalapril Proteins 0.000 claims description 20
208000035475 disorder Diseases 0.000 claims description 19
229960000873 enalapril Drugs 0.000 claims description 19
GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 claims description 19
239000000126 substance Substances 0.000 claims description 15
239000002053 C09CA06 - Candesartan Substances 0.000 claims description 14
108010066671 Enalaprilat Proteins 0.000 claims description 14
229960000932 candesartan Drugs 0.000 claims description 14
229960002680 enalaprilat Drugs 0.000 claims description 14
LZFZMUMEGBBDTC-QEJZJMRPSA-N enalaprilat (anhydrous) Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 LZFZMUMEGBBDTC-QEJZJMRPSA-N 0.000 claims description 14
101800000733 Angiotensin-2 Proteins 0.000 claims description 13
CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 claims description 13
229950006323 angiotensin ii Drugs 0.000 claims description 13
230000001105 regulatory effect Effects 0.000 claims description 13
206010039073 rheumatoid arthritis Diseases 0.000 claims description 13
239000012472 biological sample Substances 0.000 claims description 12
239000003814 drug Substances 0.000 claims description 11
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208000002678 Mucopolysaccharidoses Diseases 0.000 claims description 10
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108010083387 Saralasin Proteins 0.000 claims description 9
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FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 claims description 9
150000007523 nucleic acids Chemical group 0.000 claims description 9
230000002132 lysosomal effect Effects 0.000 claims description 8
101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims description 7
101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims description 7
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108091028043 Nucleic acid sequence Proteins 0.000 claims description 7
208000017169 kidney disease Diseases 0.000 claims description 7
238000004519 manufacturing process Methods 0.000 claims description 7
LFBBWVTUUAFKIO-RITPCOANSA-N (2r)-3-methylsulfanyl-2-[(2s)-2-methyl-3-sulfanylpropanoyl]oxypropanoic acid Chemical compound CSC[C@@H](C(O)=O)OC(=O)[C@H](C)CS LFBBWVTUUAFKIO-RITPCOANSA-N 0.000 claims description 6
RPRNBLHRKYAXSM-UHFFFAOYSA-N 2-ethyl-4-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methoxy]-5,6,7,8-tetrahydroquinoline;hydrochloride Chemical compound Cl.C=12CCCCC2=NC(CC)=CC=1OCC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=NN1 RPRNBLHRKYAXSM-UHFFFAOYSA-N 0.000 claims description 6
NPAICBCRXGSAJJ-UHFFFAOYSA-N 3,6-dihydroxyphenazine-1-carboxylic acid Chemical compound C1=CC=C2N=C3C(C(=O)O)=CC(O)=CC3=NC2=C1O NPAICBCRXGSAJJ-UHFFFAOYSA-N 0.000 claims description 6
108010076395 CGP 38560 Proteins 0.000 claims description 6
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VXFJYXUZANRPDJ-WTNASJBWSA-N Trandopril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@H]2CCCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 VXFJYXUZANRPDJ-WTNASJBWSA-N 0.000 claims description 6
YBZYNINTWCLDQA-UHKVWXOHSA-N acetic acid;(2s)-2-[[(2s)-1-[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-5-(diaminomethylideneamino)-2-[[2-(methylamino)acetyl]amino]pentanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl]amino]-3-(1h-imidazol-5-yl)prop Chemical compound O.CC(O)=O.C([C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(O)=O)C1=CC=C(O)C=C1 YBZYNINTWCLDQA-UHKVWXOHSA-N 0.000 claims description 6
KKBIUAUSZKGNOA-HNAYVOBHSA-N benzyl (2s)-2-[[(2s)-2-(acetylsulfanylmethyl)-3-(1,3-benzodioxol-5-yl)propanoyl]amino]propanoate Chemical compound O=C([C@@H](NC(=O)[C@@H](CSC(C)=O)CC=1C=C2OCOC2=CC=1)C)OCC1=CC=CC=C1 KKBIUAUSZKGNOA-HNAYVOBHSA-N 0.000 claims description 6
UQUFRFSCUYVXBM-UHFFFAOYSA-N methyl 2-hydroxy-3-[[3-(1h-imidazol-5-yl)-2-[[2-(naphthalen-1-ylmethyl)-4-oxo-4-(2-phenylethylamino)butanoyl]amino]propanoyl]amino]-5-methylhexanoate Chemical compound C=1C=CC=CC=1CCNC(=O)CC(CC=1C2=CC=CC=C2C=CC=1)C(=O)NC(C(=O)NC(CC(C)C)C(O)C(=O)OC)CC1=CN=CN1 UQUFRFSCUYVXBM-UHFFFAOYSA-N 0.000 claims description 6
239000002461 renin inhibitor Substances 0.000 claims description 6
229940086526 renin-inhibitors Drugs 0.000 claims description 6
229960001379 saralasin acetate Drugs 0.000 claims description 6
201000000596 systemic lupus erythematosus Diseases 0.000 claims description 6
RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 claims description 6
AHYHTSYNOHNUSH-HXFGRODQSA-N trandolaprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](C[C@H]2CCCC[C@@H]21)C(O)=O)C(O)=O)CC1=CC=CC=C1 AHYHTSYNOHNUSH-HXFGRODQSA-N 0.000 claims description 6
108010007859 Lisinopril Proteins 0.000 claims description 5
239000000400 angiotensin II type 1 receptor blocker Substances 0.000 claims description 5
230000003412 degenerative effect Effects 0.000 claims description 5
229960002394 lisinopril Drugs 0.000 claims description 5
RLAWWYSOJDYHDC-BZSNNMDCSA-N lisinopril Chemical compound C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 RLAWWYSOJDYHDC-BZSNNMDCSA-N 0.000 claims description 5
229960001455 quinapril Drugs 0.000 claims description 5
JSDRRTOADPPCHY-HSQYWUDLSA-N quinapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 JSDRRTOADPPCHY-HSQYWUDLSA-N 0.000 claims description 5
238000003860 storage Methods 0.000 claims description 5
210000001179 synovial fluid Anatomy 0.000 claims description 5
IQMHGRIOYXVPSE-UHFFFAOYSA-N 2-acetamido-5-[formyl(hydroxy)amino]-n-[1-[3-[5-[3-[formyl(hydroxy)amino]propyl]-3,6-dioxopiperazin-2-yl]propyl-hydroxyamino]-3-hydroxy-1-oxopropan-2-yl]pentanamide Chemical compound O=CN(O)CCCC(NC(=O)C)C(=O)NC(CO)C(=O)N(O)CCCC1NC(=O)C(CCCN(O)C=O)NC1=O IQMHGRIOYXVPSE-UHFFFAOYSA-N 0.000 claims description 4
239000012190 activator Substances 0.000 claims description 4
229960003401 ramipril Drugs 0.000 claims description 4
HDACQVRGBOVJII-JBDAPHQKSA-N ramipril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)CC1=CC=CC=C1 HDACQVRGBOVJII-JBDAPHQKSA-N 0.000 claims description 4
QKIVRALZQSUWHH-SFYZADRCSA-N (1s,2r)-2-[[2-(hydroxyamino)-2-oxoethyl]-methylcarbamoyl]cyclohexane-1-carboxylic acid Chemical compound ONC(=O)CN(C)C(=O)[C@@H]1CCCC[C@@H]1C(O)=O QKIVRALZQSUWHH-SFYZADRCSA-N 0.000 claims description 3
DEEOVDONDDERBX-MUDWFXPSSA-N (2S)-6-amino-2-[[(1S,4R,10S,19S,22S,25S,28S,31S,34R,37S,43S,46S,47S,50R,53S,56S,62S)-50-amino-43-(2-amino-2-oxoethyl)-56-(3-amino-3-oxopropyl)-10-benzyl-37-(carboxymethyl)-31-(hydroxymethyl)-28-(1H-indol-3-ylmethyl)-47,62-dimethyl-7-methylidene-22-(2-methylpropyl)-2,5,8,11,14,20,23,26,29,32,35,38,41,44,51,54,57-heptadecaoxo-53-propan-2-yl-48,60,63-trithia-3,6,9,12,15,21,24,27,30,33,36,39,42,45,52,55,58-heptadecazatetracyclo[32.24.3.34,25.015,19]tetrahexacontane-46-carbonyl]amino]hexanoic acid Chemical compound CC(C)C[C@@H]1NC(=O)[C@@H]2CCCN2C(=O)CNC(=O)[C@H](Cc2ccccc2)NC(=O)C(=C)NC(=O)[C@@H]2CS[C@@H](C)[C@@H](NC1=O)C(=O)N[C@@H](Cc1c[nH]c3ccccc13)C(=O)N[C@@H](CO)C(=O)N[C@H]1CSC[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CS[C@@H](C)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC1=O)C(=O)N[C@@H](CCCCN)C(O)=O)C(C)C)C(=O)N2 DEEOVDONDDERBX-MUDWFXPSSA-N 0.000 claims description 3
DAZBNQYTJOUXGP-UZLTUBOXSA-N (2r)-2-[[(3s)-3-[2-[[(2s)-2-[(2s,3r,4r,5r)-2-acetamido-1,4,5,6-tetrahydroxyhexan-3-yl]oxypropanoyl]amino]propanoylamino]-3-carboxypropanoyl]amino]-6,7-diamino-7-oxoheptanoic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@@H]([C@H](CO)NC(C)=O)O[C@@H](C)C(=O)NC(C)C(=O)N[C@H](C(O)=O)CC(=O)N[C@H](CCCC(N)C(N)=O)C(O)=O DAZBNQYTJOUXGP-UZLTUBOXSA-N 0.000 claims description 3
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NVXFXLSOGLFXKQ-JMSVASOKSA-N (2s)-1-[(2r,4r)-5-ethoxy-2,4-dimethyl-5-oxopentanoyl]-2,3-dihydroindole-2-carboxylic acid Chemical compound C1=CC=C2N(C(=O)[C@H](C)C[C@@H](C)C(=O)OCC)[C@H](C(O)=O)CC2=C1 NVXFXLSOGLFXKQ-JMSVASOKSA-N 0.000 claims description 3
HTBXOXWJOIKINE-RXQRSOPUSA-N (2s)-1-[(2s)-2-[[5-(2,3-dihydro-1-benzofuran-2-yl)-1-ethoxy-1-oxopentan-2-yl]amino]propanoyl]pyrrolidine-2-carboxylic acid Chemical compound O=C([C@H](C)NC(CCCC1OC2=CC=CC=C2C1)C(=O)OCC)N1CCC[C@H]1C(O)=O HTBXOXWJOIKINE-RXQRSOPUSA-N 0.000 claims description 3
QIJLJZOGPPQCOG-NFAWXSAZSA-N (2s)-1-[(2s)-3-[(2r)-2-(cyclohexanecarbonylamino)propanoyl]sulfanyl-2-methylpropanoyl]pyrrolidine-2-carboxylic acid Chemical compound N([C@H](C)C(=O)SC[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)C(=O)C1CCCCC1 QIJLJZOGPPQCOG-NFAWXSAZSA-N 0.000 claims description 3
XCLLRLKRCYZTES-PBKHYBTFSA-N (2s)-1-[2-[[1-carboxy-5-[[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]-1h-indole-2-carbonyl]amino]pentyl]amino]propanoyl]pyrrolidine-2-carboxylic acid Chemical compound C=1C=2C(OCC(O)CNC(C)C)=CC=CC=2NC=1C(=O)NCCCCC(C(O)=O)NC(C)C(=O)N1CCC[C@H]1C(O)=O XCLLRLKRCYZTES-PBKHYBTFSA-N 0.000 claims description 3
WJXAVNPIJIPGMN-PNGYUKAISA-N (2s)-2-[[(2s)-1-[(2s)-2-[[(2s,3s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-5-(diaminomethylideneamino)-2-[[2-(methylamino)acetyl]amino]pentanoyl]amino]-3-methylbutanoyl]amino]-3-(4-methoxyphenyl)propanoyl]amino]-3-methylpentanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]py Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC)C(C)C)C1=CC=C(OC)C=C1 WJXAVNPIJIPGMN-PNGYUKAISA-N 0.000 claims description 3
GKYIONYOYVKKQI-MPGHIAIKSA-N (2s)-2-[[(2s,3r)-2-(benzoylsulfanylmethyl)-3-phenylbutanoyl]amino]propanoic acid Chemical compound C([C@H](C(=O)N[C@@H](C)C(O)=O)[C@@H](C)C=1C=CC=CC=1)SC(=O)C1=CC=CC=C1 GKYIONYOYVKKQI-MPGHIAIKSA-N 0.000 claims description 3
VGLXNWGVKZBOQS-IRXDYDNUSA-N (2s)-2-[[(3r)-5-(carboxymethyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl]amino]-6-piperidin-4-ylhexanoic acid Chemical compound C([C@H](N[C@H]1CSC2=CC=CC=C2N(C1=O)CC(=O)O)C(O)=O)CCCC1CCNCC1 VGLXNWGVKZBOQS-IRXDYDNUSA-N 0.000 claims description 3
OMGPCTGQLHHVDU-SSXGPBTGSA-N (2s)-3-[(2s)-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-3-azabicyclo[2.2.2]octane-2-carboxylic acid Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](C2CCC1CC2)C(O)=O)CC1=CC=CC=C1 OMGPCTGQLHHVDU-SSXGPBTGSA-N 0.000 claims description 3
FTYVYAGWBXTWTN-ZVZYQTTQSA-N (2s)-5-tert-butyl-3-[(2s)-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-2h-1,3,4-thiadiazole-2-carboxylic acid Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](SC(=N1)C(C)(C)C)C(O)=O)CC1=CC=CC=C1 FTYVYAGWBXTWTN-ZVZYQTTQSA-N 0.000 claims description 3
XXPFSPNMUAZMMO-CRNPUGFUSA-N (2s)-n-[(2s)-2-amino-3-cyclohexylpropanoyl]-n-[(2s)-2-[[(2r)-2-benzyl-3-tert-butylsulfonylpropanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]-2-(butylamino)-3-methylbutanamide;methanesulfonic acid Chemical compound CS(O)(=O)=O.C([C@H](N)C(=O)N(C(=O)[C@H](C(C)C)NCCCC)C(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](CC=1C=CC=CC=1)CS(=O)(=O)C(C)(C)C)C1CCCCC1 XXPFSPNMUAZMMO-CRNPUGFUSA-N 0.000 claims description 3
BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 claims description 3
GGKXIITZBSPCQP-IZIWAXSGSA-N (2s,4s,5s)-5-[[(2s)-2-[[(2s)-2-benzyl-3-tert-butylsulfonylpropanoyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-n-butyl-6-cyclohexyl-4-hydroxy-2-propan-2-ylhexanamide Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)NCCCC)C(C)C)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC=1C=CC=CC=1)CS(=O)(=O)C(C)(C)C)C1CCCCC1 GGKXIITZBSPCQP-IZIWAXSGSA-N 0.000 claims description 3
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KRGPXXHMOXVMMM-CIUDSAMLSA-N (S,S,S)-nicotianamine Chemical compound [O-]C(=O)[C@@H]([NH3+])CC[NH2+][C@H](C([O-])=O)CC[NH+]1CC[C@H]1C([O-])=O KRGPXXHMOXVMMM-CIUDSAMLSA-N 0.000 claims description 3
RCEDCOCCCMIKCY-ZVCJTHDASA-N (e)-but-2-enedioic acid;octyl (2s,3as,6as)-1-[(2s)-2-[[(2s)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-3,3a,4,5,6,6a-hexahydro-2h-cyclopenta[b]pyrrole-2-carboxylate Chemical compound OC(=O)\C=C\C(O)=O.C([C@H](N[C@@H](C)C(=O)N1[C@H]2CCC[C@H]2C[C@H]1C(=O)OCCCCCCCC)C(=O)OCC)CC1=CC=CC=C1 RCEDCOCCCMIKCY-ZVCJTHDASA-N 0.000 claims description 3
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