CA2774389A1 - Methods of treating aneurysmal dilatation, blood vessel wall weakness and specifically abdominal aortic and thoracic aneurysm using matrix metalloprotease-2 inhibitors - Google Patents
Methods of treating aneurysmal dilatation, blood vessel wall weakness and specifically abdominal aortic and thoracic aneurysm using matrix metalloprotease-2 inhibitors Download PDFInfo
- Publication number
- CA2774389A1 CA2774389A1 CA2774389A CA2774389A CA2774389A1 CA 2774389 A1 CA2774389 A1 CA 2774389A1 CA 2774389 A CA2774389 A CA 2774389A CA 2774389 A CA2774389 A CA 2774389A CA 2774389 A1 CA2774389 A1 CA 2774389A1
- Authority
- CA
- Canada
- Prior art keywords
- blood vessel
- vessel wall
- inhibitors
- treatment
- aneurysm
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 94
- 206010002329 Aneurysm Diseases 0.000 title claims abstract description 33
- 210000004204 blood vessel Anatomy 0.000 title claims abstract description 33
- 239000003112 inhibitor Substances 0.000 title claims abstract description 21
- 210000000115 thoracic cavity Anatomy 0.000 title claims abstract description 21
- 239000011159 matrix material Substances 0.000 title description 10
- 230000003187 abdominal effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 208000002223 abdominal aortic aneurysm Diseases 0.000 claims abstract description 22
- 208000007474 aortic aneurysm Diseases 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 239000005541 ACE inhibitor Substances 0.000 claims abstract description 9
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims abstract description 9
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims abstract description 9
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims abstract description 9
- 102000008873 Angiotensin II receptor Human genes 0.000 claims abstract description 5
- 108050000824 Angiotensin II receptor Proteins 0.000 claims abstract description 5
- 239000003937 drug carrier Substances 0.000 claims abstract description 4
- -1 aprosartan Chemical compound 0.000 claims description 41
- 230000000694 effects Effects 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 11
- 229940124761 MMP inhibitor Drugs 0.000 claims description 9
- 108010072220 Cyclophilin A Proteins 0.000 claims description 4
- 102100034539 Peptidyl-prolyl cis-trans isomerase A Human genes 0.000 claims description 4
- 239000003087 receptor blocking agent Substances 0.000 claims description 4
- 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
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 claims description 3
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 claims description 3
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 claims description 3
- 239000002083 C09CA01 - Losartan Substances 0.000 claims description 3
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 3
- 239000002947 C09CA04 - Irbesartan Substances 0.000 claims description 3
- 239000002053 C09CA06 - Candesartan Substances 0.000 claims description 3
- 108010061435 Enalapril Proteins 0.000 claims description 3
- 108010007859 Lisinopril Proteins 0.000 claims description 3
- 229960004530 benazepril Drugs 0.000 claims description 3
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 claims description 3
- 229960000932 candesartan Drugs 0.000 claims description 3
- 229960000830 captopril Drugs 0.000 claims description 3
- 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 3
- 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 3
- 229960000873 enalapril Drugs 0.000 claims description 3
- 229960002490 fosinopril Drugs 0.000 claims description 3
- 229960002198 irbesartan Drugs 0.000 claims description 3
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 claims description 3
- 229960002394 lisinopril Drugs 0.000 claims description 3
- 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 3
- 229960004773 losartan Drugs 0.000 claims description 3
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 3
- 229960002582 perindopril Drugs 0.000 claims description 3
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 claims description 3
- 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 3
- 229960001455 quinapril Drugs 0.000 claims description 3
- 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 3
- 229960003401 ramipril Drugs 0.000 claims description 3
- 229960004699 valsartan Drugs 0.000 claims description 3
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims description 3
- IAIDUHCBNLFXEF-MNEFBYGVSA-N zofenopril Chemical compound C([C@@H](C)C(=O)N1[C@@H](C[C@@H](C1)SC=1C=CC=CC=1)C(O)=O)SC(=O)C1=CC=CC=C1 IAIDUHCBNLFXEF-MNEFBYGVSA-N 0.000 claims description 3
- 229960002769 zofenopril Drugs 0.000 claims description 3
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 claims 1
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 claims 1
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 27
- 108091007504 ADAM10 Proteins 0.000 abstract description 8
- 230000005764 inhibitory process Effects 0.000 abstract description 7
- 102000005862 Angiotensin II Human genes 0.000 abstract description 5
- 101800000733 Angiotensin-2 Proteins 0.000 abstract description 5
- 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 abstract description 5
- 229950006323 angiotensin ii Drugs 0.000 abstract description 5
- 230000031018 biological processes and functions Effects 0.000 abstract description 4
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 238000000338 in vitro Methods 0.000 abstract description 3
- 102000036664 ADAM10 Human genes 0.000 abstract 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 90
- 229910052757 nitrogen Inorganic materials 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 56
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 44
- 235000019439 ethyl acetate Nutrition 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 229910001868 water Inorganic materials 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- 241001465754 Metazoa Species 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 239000003795 chemical substances by application Substances 0.000 description 22
- 102100039673 Disintegrin and metalloproteinase domain-containing protein 10 Human genes 0.000 description 21
- 101150041968 CDC13 gene Proteins 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 125000001424 substituent group Chemical group 0.000 description 18
- 125000003118 aryl group Chemical group 0.000 description 17
- 201000010099 disease Diseases 0.000 description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 17
- 241000699670 Mus sp. Species 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 125000005842 heteroatom Chemical group 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000011161 development Methods 0.000 description 14
- 230000018109 developmental process Effects 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 108010070047 Notch Receptors Proteins 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 12
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 12
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 12
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 12
- 230000010412 perfusion Effects 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 210000000709 aorta Anatomy 0.000 description 11
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- 101000959356 Homo sapiens Disintegrin and metalloproteinase domain-containing protein 10 Proteins 0.000 description 10
- 102000014736 Notch Human genes 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 9
- 229960003722 doxycycline Drugs 0.000 description 9
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 description 9
- 238000003818 flash chromatography Methods 0.000 description 9
- 125000001183 hydrocarbyl group Chemical group 0.000 description 9
- 125000003367 polycyclic group Polymers 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 9
- 101100081489 Drosophila melanogaster Obp83a gene Proteins 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 125000001041 indolyl group Chemical group 0.000 description 8
- 125000000842 isoxazolyl group Chemical group 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 125000003373 pyrazinyl group Chemical group 0.000 description 8
- 125000004076 pyridyl group Chemical group 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 7
- 230000015556 catabolic process Effects 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 125000002541 furyl group Chemical group 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 238000003306 harvesting Methods 0.000 description 7
- 125000002883 imidazolyl group Chemical group 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 125000001544 thienyl group Chemical group 0.000 description 7
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 6
- 102000016942 Elastin Human genes 0.000 description 6
- 108010014258 Elastin Proteins 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 102000005741 Metalloproteases Human genes 0.000 description 6
- 108010006035 Metalloproteases Proteins 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 6
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 6
- 239000004305 biphenyl Substances 0.000 description 6
- 235000010290 biphenyl Nutrition 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229920002549 elastin Polymers 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 125000005956 isoquinolyl group Chemical group 0.000 description 6
- 125000001786 isothiazolyl group Chemical group 0.000 description 6
- 230000023886 lateral inhibition Effects 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 6
- 125000003226 pyrazolyl group Chemical group 0.000 description 6
- 125000001725 pyrenyl group Chemical group 0.000 description 6
- 125000005493 quinolyl group Chemical group 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 125000003831 tetrazolyl group Chemical group 0.000 description 6
- DLJCHYZYQWEVGJ-LURJTMIESA-N (2r)-4-[(2-methylpropan-2-yl)oxycarbonyl]-3-sulfonylpiperazine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCN[C@H](C(O)=O)C1=S(=O)=O DLJCHYZYQWEVGJ-LURJTMIESA-N 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 108091022885 ADAM Proteins 0.000 description 5
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 5
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 5
- 102000016387 Pancreatic elastase Human genes 0.000 description 5
- 108010067372 Pancreatic elastase Proteins 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 125000003710 aryl alkyl group Chemical group 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- 238000003304 gavage Methods 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 239000002207 metabolite Substances 0.000 description 5
- 230000001272 neurogenic effect Effects 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 229910017912 NH2OH Inorganic materials 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012867 bioactive agent Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000010779 crude oil Substances 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000005415 substituted alkoxy group Chemical group 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- IIZGWFQKLVCLLA-SNVBAGLBSA-N (2r)-1,4-bis[(2-methylpropan-2-yl)oxycarbonyl]piperazine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(O)=O)C1 IIZGWFQKLVCLLA-SNVBAGLBSA-N 0.000 description 3
- WNSDZBQLMGKPQS-RZFWHQLPSA-N (2r)-piperazine-1,4-diium-2-carboxylic acid;dichloride Chemical compound Cl.Cl.OC(=O)[C@H]1CNCCN1 WNSDZBQLMGKPQS-RZFWHQLPSA-N 0.000 description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 3
- JSSXHAMIXJGYCS-SCSAIBSYSA-N (R)-piperazine-2-carboxylic acid Chemical compound [O-]C(=O)[C@H]1CNCC[NH2+]1 JSSXHAMIXJGYCS-SCSAIBSYSA-N 0.000 description 3
- NBWITVOFJWJOEF-UHFFFAOYSA-N 4-(4-chlorophenoxy)-3,5-difluorobenzenesulfonyl chloride Chemical compound FC1=CC(S(Cl)(=O)=O)=CC(F)=C1OC1=CC=C(Cl)C=C1 NBWITVOFJWJOEF-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 102000029791 ADAM Human genes 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 108010068682 Cyclophilins Proteins 0.000 description 3
- 102000001493 Cyclophilins Human genes 0.000 description 3
- 102100031111 Disintegrin and metalloproteinase domain-containing protein 17 Human genes 0.000 description 3
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 3
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 3
- 241000282414 Homo sapiens Species 0.000 description 3
- 108010016165 Matrix Metalloproteinase 2 Proteins 0.000 description 3
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 102000005650 Notch Receptors Human genes 0.000 description 3
- 101800001775 Nuclear inclusion protein A Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 125000004104 aryloxy group Chemical group 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000036983 biotransformation Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 239000000134 cyclophilin inhibitor Substances 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000002350 laparotomy Methods 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 230000004766 neurogenesis Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000008389 polyethoxylated castor oil Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 235000010288 sodium nitrite Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 3
- 230000036642 wellbeing Effects 0.000 description 3
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- QPLVBFYJVREOLP-SSDOTTSWSA-N (2r)-4-(morpholine-4-carbonyl)-3-sulfonylpiperazine-2-carboxamide Chemical compound O=S(=O)=C1[C@@H](C(=O)N)NCCN1C(=O)N1CCOCC1 QPLVBFYJVREOLP-SSDOTTSWSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- BRYCUMKDWMEGMK-SCSAIBSYSA-N (R)-piperazine-2-carboxamide Chemical class NC(=O)[C@H]1CNCCN1 BRYCUMKDWMEGMK-SCSAIBSYSA-N 0.000 description 2
- PTTUMBGORBMNBN-UHFFFAOYSA-N 1,2,3-trifluoro-5-nitrobenzene Chemical compound [O-][N+](=O)C1=CC(F)=C(F)C(F)=C1 PTTUMBGORBMNBN-UHFFFAOYSA-N 0.000 description 2
- PKLBCWDGWDUIJT-UHFFFAOYSA-N 1,3-difluoro-2-(4-fluorophenoxy)-5-nitrobenzene Chemical compound FC1=CC([N+](=O)[O-])=CC(F)=C1OC1=CC=C(F)C=C1 PKLBCWDGWDUIJT-UHFFFAOYSA-N 0.000 description 2
- QKNSGUCCNZBAAJ-LLVKDONJSA-N 1-o,4-o-ditert-butyl 2-o-methyl (2r)-piperazine-1,2,4-tricarboxylate Chemical compound COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C QKNSGUCCNZBAAJ-LLVKDONJSA-N 0.000 description 2
- BFNHXLOKPAWFPH-UHFFFAOYSA-N 2-(4-chlorophenoxy)-1,3-difluoro-5-nitrobenzene Chemical compound FC1=CC([N+](=O)[O-])=CC(F)=C1OC1=CC=C(Cl)C=C1 BFNHXLOKPAWFPH-UHFFFAOYSA-N 0.000 description 2
- HSEHKULCGSMHAE-UHFFFAOYSA-N 3,4,5-trifluorobenzenesulfonyl chloride Chemical compound FC1=CC(S(Cl)(=O)=O)=CC(F)=C1F HSEHKULCGSMHAE-UHFFFAOYSA-N 0.000 description 2
- ZSMNCJYXFNBIOD-UHFFFAOYSA-N 3,5-difluoro-4-(4-fluorophenoxy)aniline Chemical compound FC1=CC(N)=CC(F)=C1OC1=CC=C(F)C=C1 ZSMNCJYXFNBIOD-UHFFFAOYSA-N 0.000 description 2
- AVVIFPBMJCPPHR-UHFFFAOYSA-N 3,5-difluoro-4-(4-fluorophenoxy)benzenesulfonyl chloride Chemical compound C1=CC(F)=CC=C1OC1=C(F)C=C(S(Cl)(=O)=O)C=C1F AVVIFPBMJCPPHR-UHFFFAOYSA-N 0.000 description 2
- TVINDEPPMFUWBQ-UHFFFAOYSA-N 4-(4-chlorophenoxy)-3,5-difluoroaniline Chemical compound FC1=CC(N)=CC(F)=C1OC1=CC=C(Cl)C=C1 TVINDEPPMFUWBQ-UHFFFAOYSA-N 0.000 description 2
- 108091007505 ADAM17 Proteins 0.000 description 2
- 102100027995 Collagenase 3 Human genes 0.000 description 2
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 2
- 229940122806 Cyclophilin inhibitor Drugs 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- 206010020880 Hypertrophy Diseases 0.000 description 2
- 102000001776 Matrix metalloproteinase-9 Human genes 0.000 description 2
- 102100023181 Neurogenic locus notch homolog protein 1 Human genes 0.000 description 2
- 108700037638 Neurogenic locus notch homolog protein 1 Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 108091006629 SLC13A2 Proteins 0.000 description 2
- 229910006069 SO3H Inorganic materials 0.000 description 2
- 102100030416 Stromelysin-1 Human genes 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 241000269370 Xenopus <genus> Species 0.000 description 2
- 125000005957 acrydinyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 210000004177 elastic tissue Anatomy 0.000 description 2
- 210000002257 embryonic structure Anatomy 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000003838 furazanyl group Chemical group 0.000 description 2
- 238000001030 gas--liquid chromatography Methods 0.000 description 2
- 230000002068 genetic effect Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000004777 loss-of-function mutation Effects 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 210000003716 mesoderm Anatomy 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 2
- ZBYFDUSYNDLSND-ZJIMSODOSA-N methyl (2r)-piperazine-2-carboxylate;dihydrochloride Chemical compound Cl.Cl.COC(=O)[C@H]1CNCCN1 ZBYFDUSYNDLSND-ZJIMSODOSA-N 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 210000000653 nervous system Anatomy 0.000 description 2
- 210000003061 neural cell Anatomy 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- LBQAJLBSGOBDQF-UHFFFAOYSA-N nitro azanylidynemethanesulfonate Chemical compound [O-][N+](=O)OS(=O)(=O)C#N LBQAJLBSGOBDQF-UHFFFAOYSA-N 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000006103 sulfonylation Effects 0.000 description 2
- 238000005694 sulfonylation reaction Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 102000035160 transmembrane proteins Human genes 0.000 description 2
- 108091005703 transmembrane proteins Proteins 0.000 description 2
- 102000027257 transmembrane receptors Human genes 0.000 description 2
- 108091008578 transmembrane receptors Proteins 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 210000005166 vasculature Anatomy 0.000 description 2
- 230000003313 weakening effect Effects 0.000 description 2
- 210000001325 yolk sac Anatomy 0.000 description 2
- YRYAXQJXMBETAT-SSDOTTSWSA-N (2r)-4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-ium-2-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN[C@@H](C(O)=O)C1 YRYAXQJXMBETAT-SSDOTTSWSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 1
- PYHXGXCGESYPCW-UHFFFAOYSA-M 2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C(=O)[O-])C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-M 0.000 description 1
- WUHPPPMZCRKDAI-UHFFFAOYSA-N 2-(4-cyanophenoxy)-3-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=CC(S(Cl)(=O)=O)=C1OC1=CC=C(C#N)C=C1 WUHPPPMZCRKDAI-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
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 1
- VKUYLANQOAKALN-UHFFFAOYSA-N 2-[benzyl-(4-methoxyphenyl)sulfonylamino]-n-hydroxy-4-methylpentanamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N(C(CC(C)C)C(=O)NO)CC1=CC=CC=C1 VKUYLANQOAKALN-UHFFFAOYSA-N 0.000 description 1
- WAXLTLPGJRDRPC-ZCFIWIBFSA-N 2-methoxyethyl (3R)-3-carbamoyl-2-sulfonylpiperazine-1-carboxylate Chemical compound S(=O)(=O)=C1[C@H](NCCN1C(=O)OCCOC)C(=O)N WAXLTLPGJRDRPC-ZCFIWIBFSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- SZRDJHHKIJHJHQ-UHFFFAOYSA-N 3,4,5-trifluoroaniline Chemical compound NC1=CC(F)=C(F)C(F)=C1 SZRDJHHKIJHJHQ-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- PDAYRCHIAPCRRD-UHFFFAOYSA-N 4-(4-fluorophenoxy)benzenesulfonyl chloride Chemical compound C1=CC(F)=CC=C1OC1=CC=C(S(Cl)(=O)=O)C=C1 PDAYRCHIAPCRRD-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
- GILJYDFPKGMYDW-UHFFFAOYSA-N 5-diazo-1,2,3-trifluorocyclohexa-1,3-diene Chemical compound FC1=C(F)C(F)=CC(=[N+]=[N-])C1 GILJYDFPKGMYDW-UHFFFAOYSA-N 0.000 description 1
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 229910000906 Bronze Inorganic materials 0.000 description 1
- 101100337060 Caenorhabditis elegans glp-1 gene Proteins 0.000 description 1
- 101100074828 Caenorhabditis elegans lin-12 gene Proteins 0.000 description 1
- 101100378457 Caenorhabditis elegans sup-17 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108050005238 Collagenase 3 Proteins 0.000 description 1
- 101150014361 Delta gene Proteins 0.000 description 1
- 101800001224 Disintegrin Proteins 0.000 description 1
- 108700032073 Drosophila KUZ Proteins 0.000 description 1
- 241000255601 Drosophila melanogaster Species 0.000 description 1
- 239000001263 FEMA 3042 Substances 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 101001108314 Homo sapiens Nuclear receptor-binding protein Proteins 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical class Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- ATIPDCIQTUXABX-UWVGGRQHSA-N Lys-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CCCCN ATIPDCIQTUXABX-UWVGGRQHSA-N 0.000 description 1
- 108010076503 Matrix Metalloproteinase 13 Proteins 0.000 description 1
- 108010016160 Matrix Metalloproteinase 3 Proteins 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 206010028391 Musculoskeletal Pain Diseases 0.000 description 1
- 102000047918 Myelin Basic Human genes 0.000 description 1
- 101710107068 Myelin basic protein Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100030411 Neutrophil collagenase Human genes 0.000 description 1
- 101710118230 Neutrophil collagenase Proteins 0.000 description 1
- 102000056189 Neutrophil collagenases Human genes 0.000 description 1
- 108030001564 Neutrophil collagenases Proteins 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229910005948 SO2Cl Inorganic materials 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 101710108790 Stromelysin-1 Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- 208000000491 Tendinopathy Diseases 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- 102100040247 Tumor necrosis factor Human genes 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 238000011366 aggressive therapy Methods 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
- 235000010443 alginic acid Nutrition 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000005530 alkylenedioxy group Chemical group 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000010974 bronze 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000004900 c-terminal fragment Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000005518 carboxamido group Chemical group 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000008614 cellular interaction Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical compound C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid Chemical compound OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 108010011222 cyclo(Arg-Pro) Proteins 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 125000004415 heterocyclylalkyl group Chemical group 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
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000008611 intercellular interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([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
- 239000003446 ligand Substances 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 238000000386 microscopy Methods 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
- 239000003607 modifier Substances 0.000 description 1
- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000021268 myoblast fusion Effects 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000003988 neural development Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000004031 neuronal differentiation Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 208000030613 peripheral artery disease Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- BRYCUMKDWMEGMK-UHFFFAOYSA-N piperazine-2-carboxamide Chemical class NC(=O)C1CNCCN1 BRYCUMKDWMEGMK-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007261 regionalization Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000002023 somite Anatomy 0.000 description 1
- 230000033451 somitogenesis Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 229940033123 tannic acid Drugs 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
- 201000004415 tendinitis Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 239000002447 tumor necrosis factor alpha converting enzyme inhibitor Substances 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24784309P | 2009-10-01 | 2009-10-01 | |
| US61/247,843 | 2009-10-01 | ||
| PCT/US2010/050907 WO2011041545A1 (en) | 2009-10-01 | 2010-09-30 | Methods of treating aneurysmal dilatation, blood vessel wall weakness and specifically abdominal aortic and thoracic aneurysm using matrix metalloprotease-2 inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2774389A1 true CA2774389A1 (en) | 2011-04-07 |
Family
ID=43034492
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2774389A Abandoned CA2774389A1 (en) | 2009-10-01 | 2010-09-30 | Methods of treating aneurysmal dilatation, blood vessel wall weakness and specifically abdominal aortic and thoracic aneurysm using matrix metalloprotease-2 inhibitors |
Country Status (6)
| Country | Link |
|---|---|
| US (2) | US20110082114A1 (cg-RX-API-DMAC7.html) |
| EP (1) | EP2482817A1 (cg-RX-API-DMAC7.html) |
| JP (1) | JP2013506684A (cg-RX-API-DMAC7.html) |
| CN (1) | CN102639134A (cg-RX-API-DMAC7.html) |
| CA (1) | CA2774389A1 (cg-RX-API-DMAC7.html) |
| WO (1) | WO2011041545A1 (cg-RX-API-DMAC7.html) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013506684A (ja) * | 2009-10-01 | 2013-02-28 | シンフォニー エボリューション， インコーポレイテッド | マトリックスメタロプロテアーゼ−２阻害剤を用いた、動脈瘤性拡張、血管壁脆弱性、特に腹部大動脈瘤および胸部動脈瘤を治療する方法 |
| US9629891B2 (en) | 2011-10-17 | 2017-04-25 | Nationwide Children's Hospital, Inc. | Products and methods for aortic abdominal aneurysm |
| EP3693460A1 (en) * | 2012-07-27 | 2020-08-12 | Ionis Pharmaceuticals, Inc. | Modulation of renin-angiotensin system (ras) related diseases by angiotensinogen |
| WO2014028334A1 (en) * | 2012-08-11 | 2014-02-20 | Symphony Evolution, Inc. | Selective mmp inhibitors |
| US9791461B2 (en) | 2012-10-30 | 2017-10-17 | Tohoku University | Method for testing for cardiovascular disease with cyclophilin A |
| BR122020023854B1 (pt) | 2015-10-08 | 2022-11-29 | Ionis Pharmaceuticals, Inc | Composto compreendendo oligonucleotídeo modificado e seu uso, uso do oligonucleotídeo modificado, composição e seu uso |
| US11376248B2 (en) * | 2017-06-30 | 2022-07-05 | Georgia State University Research Foundation, Inc. | Treatment of aneurysms |
| CN107417629B (zh) * | 2017-08-09 | 2020-02-07 | 苏州楚凯药业有限公司 | 动脉瘤抑制剂xl784的制备方法 |
| US11273148B2 (en) | 2017-09-01 | 2022-03-15 | The Johns Hopkins University | Targeted epigenetic therapy for inherited aortic aneurysm condition |
| CN108947850B (zh) * | 2018-07-23 | 2021-05-18 | 蚌埠中实化学技术有限公司 | 一种3,4,5-三氟苯胺的制备方法 |
| WO2021063366A1 (zh) * | 2019-09-30 | 2021-04-08 | 中国科学院上海药物研究所 | 用于治疗动脉相关疾病的药物及其用途 |
| CN111500721B (zh) * | 2020-04-20 | 2022-11-29 | 青岛大学附属医院 | Tace在腹主动脉瘤腔内修复术后内漏诊断中的应用 |
| ES2990026T3 (es) | 2020-11-18 | 2024-11-28 | Ionis Pharmaceuticals Inc | Compuestos y métodos para modular la expresión del angiotensinógeno |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU723836B2 (en) | 1996-08-29 | 2000-09-07 | Regents Of The University Of California, The | Kuz, a novel family of metalloproteases |
| US5922546A (en) | 1997-08-25 | 1999-07-13 | Smithkline Beecham Corporation | Human disintegrin metalloprotease KUZ gene |
| ATE225187T1 (de) * | 1997-12-23 | 2002-10-15 | Warner Lambert Co | Ace hemmer/matrix metalloproteinase hemmer- arzneimittelkombinationen |
| AUPP584198A0 (en) * | 1998-09-14 | 1998-10-08 | Fujisawa Pharmaceutical Co., Ltd. | New use |
| AU2002241343A1 (en) * | 2002-03-29 | 2003-10-13 | Anges Mg, Inc. | Decoy compositions for treating and preventing brain diseases and disorders |
| AU2003237532B2 (en) | 2002-06-12 | 2009-07-30 | Symphony Evolution, Inc. | Human ADAM-10 inhibitors |
| US7396540B2 (en) * | 2003-04-25 | 2008-07-08 | Medtronic Vascular, Inc. | In situ blood vessel and aneurysm treatment |
| US7371228B2 (en) * | 2003-09-19 | 2008-05-13 | Medtronic Vascular, Inc. | Delivery of therapeutics to treat aneurysms |
| US20050266043A1 (en) * | 2004-05-27 | 2005-12-01 | Medtronic Vascular, Inc. | Methods and compounds for treatment of aneurysmal tissue |
| WO2007016482A2 (en) * | 2005-07-29 | 2007-02-08 | Imperial Innovations Limited | Mutant timp-3 |
| US8597646B2 (en) * | 2005-10-25 | 2013-12-03 | The Johns Hopkins University | Methods and compositons featuring TGF-beta antagonists for the treatment of marfan syndrome and associated disorders |
| JP2013506684A (ja) * | 2009-10-01 | 2013-02-28 | シンフォニー エボリューション， インコーポレイテッド | マトリックスメタロプロテアーゼ−２阻害剤を用いた、動脈瘤性拡張、血管壁脆弱性、特に腹部大動脈瘤および胸部動脈瘤を治療する方法 |
-
2010
- 2010-09-30 JP JP2012532316A patent/JP2013506684A/ja active Pending
- 2010-09-30 US US12/895,073 patent/US20110082114A1/en not_active Abandoned
- 2010-09-30 EP EP10762834A patent/EP2482817A1/en not_active Withdrawn
- 2010-09-30 WO PCT/US2010/050907 patent/WO2011041545A1/en not_active Ceased
- 2010-09-30 CA CA2774389A patent/CA2774389A1/en not_active Abandoned
- 2010-09-30 US US13/497,726 patent/US20120270884A1/en not_active Abandoned
- 2010-09-30 CN CN2010800545319A patent/CN102639134A/zh active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| US20110082114A1 (en) | 2011-04-07 |
| WO2011041545A1 (en) | 2011-04-07 |
| US20120270884A1 (en) | 2012-10-25 |
| JP2013506684A (ja) | 2013-02-28 |
| EP2482817A1 (en) | 2012-08-08 |
| CN102639134A (zh) | 2012-08-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2774389A1 (en) | Methods of treating aneurysmal dilatation, blood vessel wall weakness and specifically abdominal aortic and thoracic aneurysm using matrix metalloprotease-2 inhibitors | |
| EP1511488B1 (en) | Human adam-10 inhibitors | |
| JP6916795B2 (ja) | Ｌｓｄ１阻害剤 | |
| CZ173398A3 (cs) | Inhibitory metaloproteinasy, farmaceutické prostředky je obsahující a jejich farmaceutické použití, způsob a meziprodukty pro jejich výrobu | |
| EP3464271A1 (en) | Pyrazole derivatives as plasma kallikrein inhibitors | |
| CZ20012637A3 (cs) | 2,3,4,5-tetrahydro-1H[1,4]benzodiazepin-3-hydroxamové kyseliny jako inhibitory metaloproteináz mezibuněčné hmoty | |
| JP4427328B2 (ja) | ヒト−ａｄａｍ−１０インヒビター | |
| CN103221386A (zh) | 基质金属蛋白酶抑制剂 | |
| CA2874950A1 (en) | Cycloalkyl ether compounds and their use as bace inhibitors | |
| AU2003297364B2 (en) | Inhibitors of TACE | |
| AU5046600A (en) | Oxazaheterocycles as protease inhibitors | |
| AU2019373324B2 (en) | Novel pyridazines | |
| EP1194428B1 (en) | Heteroaryl protease inhibitors and diagnostic imaging agents | |
| EP1613319A2 (en) | Substituted phenyl acetamides and their use as protease inhibitors | |
| WO2016027284A2 (en) | Piperidine ureas as cathepsin cysteine protease inhibitors | |
| KR20010101731A (ko) | 헤테로아릴 아세틸렌계 설폰아미드 및 포스핀산 아미드하이드록삼산 티에이씨이 억제제 | |
| HK1257006A1 (en) | Derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine and uses thereof | |
| HK1257006B (en) | Derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine and uses thereof | |
| WO2008147764A1 (en) | Mmp inhibitors and methods of use thereof | |
| MXPA01007574A (en) | Acetylenic sulfonamide thiol tace inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 20160930 |