WO1997021726A1 - Agents for promoting bone formation - Google Patents
Agents for promoting bone formation Download PDFInfo
- Publication number
- WO1997021726A1 WO1997021726A1 PCT/EP1996/005380 EP9605380W WO9721726A1 WO 1997021726 A1 WO1997021726 A1 WO 1997021726A1 EP 9605380 W EP9605380 W EP 9605380W WO 9721726 A1 WO9721726 A1 WO 9721726A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- bone formation
- carbon atoms
- promoting bone
- compound represented
- Prior art date
Links
- 230000011164 ossification Effects 0.000 title claims abstract description 57
- 230000001737 promoting effect Effects 0.000 title claims abstract description 52
- 150000001875 compounds Chemical class 0.000 claims abstract description 135
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 39
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 27
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 16
- RGNVSYKVCGAEHK-GUBZILKMSA-N (3s)-3-[[2-[[(2s)-2-[(2-aminoacetyl)amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-4-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-oxobutanoic acid Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(O)=O RGNVSYKVCGAEHK-GUBZILKMSA-N 0.000 claims abstract description 15
- 108010034892 glycyl-arginyl-glycyl-aspartyl-serine Proteins 0.000 claims abstract description 15
- 108010059557 kistrin Proteins 0.000 claims abstract description 15
- ZTYNVDHJNRIRLL-FWZKYCSMSA-N rhodostomin Chemical compound C([C@H]1C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H]2C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(=O)N3CCC[C@H]3C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCSC)C(=O)N3CCC[C@H]3C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CSSC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H](CC=2NC=NC=2)C(O)=O)[C@@H](C)O)=O)CSSC[C@H]2C(=O)N[C@H]3CSSC[C@@H](C(NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@@H]2CCCN2C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H]2NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]4CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)CN)CSSC2)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N2CCC[C@H]2C(=O)N[C@H](C(N4)=O)CSSC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC3=O)C(=O)N[C@@H](CCCCN)C(=O)N1)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=CC=C1 ZTYNVDHJNRIRLL-FWZKYCSMSA-N 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 55
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000004480 active ingredient Substances 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 5
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 abstract description 11
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 9
- 229920001184 polypeptide Polymers 0.000 abstract description 6
- 150000001413 amino acids Chemical group 0.000 abstract description 4
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 3
- 210000000988 bone and bone Anatomy 0.000 description 52
- 210000004027 cell Anatomy 0.000 description 24
- 230000002308 calcification Effects 0.000 description 13
- 210000000963 osteoblast Anatomy 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 210000002997 osteoclast Anatomy 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 8
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 0 C*Oc1ccc(CC(C(O)=O)[Mn]C(OCc2ccccc2)=O)cc1 Chemical compound C*Oc1ccc(CC(C(O)=O)[Mn]C(OCc2ccccc2)=O)cc1 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 102000006495 integrins Human genes 0.000 description 7
- 108010044426 integrins Proteins 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 230000001605 fetal effect Effects 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 241000283690 Bos taurus Species 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 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
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102000016359 Fibronectins Human genes 0.000 description 4
- 108010067306 Fibronectins Proteins 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 210000002805 bone matrix Anatomy 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 108010053299 glycyl-arginyl-glycyl-aspartyl-seryl-proline Proteins 0.000 description 4
- 208000010392 Bone Fractures Diseases 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 210000004292 cytoskeleton Anatomy 0.000 description 3
- 210000003754 fetus Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000002054 transplantation Methods 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- 208000018083 Bone metabolism disease Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 2
- 108010080379 Fibrin Tissue Adhesive Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 230000010062 adhesion mechanism Effects 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005261 aspartic acid Drugs 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000002316 cosmetic surgery Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 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 2
- 229960003957 dexamethasone Drugs 0.000 description 2
- 229940113088 dimethylacetamide Drugs 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 2
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 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
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- NTEDOEBWPRVVSG-XUXIUFHCSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[2-[[(2s)-2-[(2-aminoacetyl)amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]pyrrolidine-2-carboxylic acid Chemical compound NC(N)=NCCC[C@H](NC(=O)CN)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N1CCC[C@H]1C(O)=O NTEDOEBWPRVVSG-XUXIUFHCSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N 1-propanol Substances CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- WAKFRZBXTKUFIW-UHFFFAOYSA-N 2-bromo-2-phenylacetic acid Chemical compound OC(=O)C(Br)C1=CC=CC=C1 WAKFRZBXTKUFIW-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- GLAJVFVWRKTVLL-YIZRAAEISA-N C[C@@H]1[C@H](C)C=C[C@H](C)C1 Chemical compound C[C@@H]1[C@H](C)C=C[C@H](C)C1 GLAJVFVWRKTVLL-YIZRAAEISA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 108010069514 Cyclic Peptides Proteins 0.000 description 1
- 102000001189 Cyclic Peptides Human genes 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
- 108700021041 Disintegrin Proteins 0.000 description 1
- -1 FMOC amino acid Chemical class 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 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 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 102000008607 Integrin beta3 Human genes 0.000 description 1
- 108010020950 Integrin beta3 Proteins 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N O=COCc1ccccc1 Chemical compound O=COCc1ccccc1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 102000004264 Osteopontin Human genes 0.000 description 1
- 108010081689 Osteopontin Proteins 0.000 description 1
- 208000006735 Periostitis Diseases 0.000 description 1
- 102000007365 Sialoglycoproteins Human genes 0.000 description 1
- 108010032838 Sialoglycoproteins Proteins 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
- 108060008245 Thrombospondin Proteins 0.000 description 1
- 102000002938 Thrombospondin Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 239000003875 Wang resin Substances 0.000 description 1
- NERFNHBZJXXFGY-UHFFFAOYSA-N [4-[(4-methylphenyl)methoxy]phenyl]methanol Chemical group C1=CC(C)=CC=C1COC1=CC=C(CO)C=C1 NERFNHBZJXXFGY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- RGCKGOZRHPZPFP-UHFFFAOYSA-N alizarin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- DHCLVCXQIBBOPH-UHFFFAOYSA-N beta-glycerol phosphate Natural products OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 1
- GHRQXJHBXKYCLZ-UHFFFAOYSA-L beta-glycerolphosphate Chemical compound [Na+].[Na+].CC(CO)OOP([O-])([O-])=O GHRQXJHBXKYCLZ-UHFFFAOYSA-L 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 210000002449 bone cell Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- KAKKHKRHCKCAGH-UHFFFAOYSA-L disodium;(4-nitrophenyl) phosphate;hexahydrate Chemical compound O.O.O.O.O.O.[Na+].[Na+].[O-][N+](=O)C1=CC=C(OP([O-])([O-])=O)C=C1 KAKKHKRHCKCAGH-UHFFFAOYSA-L 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 201000010934 exostosis Diseases 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 201000010930 hyperostosis Diseases 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000006371 metabolic abnormality Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 208000005368 osteomalacia Diseases 0.000 description 1
- 208000002865 osteopetrosis Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 210000003460 periosteum Anatomy 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 239000003998 snake venom Substances 0.000 description 1
- RUYANEADGUFWRJ-UHFFFAOYSA-M sodium;(4-nitrophenyl) hydrogen phosphate Chemical compound [Na+].OP([O-])(=O)OC1=CC=C([N+]([O-])=O)C=C1 RUYANEADGUFWRJ-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000002653 sulfanylmethyl group Chemical group [H]SC([H])([H])[*] 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 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 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/07—Tetrapeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- 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
-
- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0815—Tripeptides with the first amino acid being basic
- C07K5/0817—Tripeptides with the first amino acid being basic the first amino acid being Arg
-
- 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
- C07K5/10—Tetrapeptides
- C07K5/1019—Tetrapeptides with the first amino acid being basic
-
- 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
- C07K5/10—Tetrapeptides
- C07K5/1024—Tetrapeptides with the first amino acid being heterocyclic
Definitions
- This invention relates to a promoting agent for bone formation which comprises a peptide or polypeptide containing the amino acid sequence consisting of ArgGlyAsp (hereinafter referred to as RGD sequence) in the molecule. Further, the invention relates to a prophylactic and therapeutic method for bone fracture utilizing a promoting agent for bone formation comprising the peptide or polypeptide containing the said RGD sequence. Also, the invention relates to a novel cyclic peptide containing the said RGD sequence. And further, it relates to a promoting agent for bone formation which comprises a compound represented by the general formulae (IX) , (X) , (XI) and (XII) .
- Bone is composed of outer cortical bone and inner trabecular bone.
- the function of bone in living body is to maintain a given shape as a skeleton and to store various inorganic substances such as calcium, phosphoric acid and the like. Bone may apparently appear to be a tissue with less variability, but actually old bone is adsorbed and instead new bone is formed. This is usually referred to as bone reformation.
- the bone reformation can be accomplished by coupling of osteoclasts controlling bone adsorption with osteoblasts controlling bone formation as both can primarily participate in therein.
- osteoblasts are not limited to bone formation solely, but it is related to differentiation and activation of osteoclasts and osteoblasts may play a role as a control center in cellular bone reconstruction.
- Those diseases generally referred to as bone metabolism diseases may include osteoporosis, Beh ⁇ et disease, osteo- malacia, hyperostosis and osteopetrosis .
- osteoporosis is the most frequently developed disease and frequency of its occurrence appears to increase with senescence so that the diagnosis and effective therapy thereof have been earnestly desired.
- the bone metabolism diseases mean those diseases wherein bone cells have specific metabolic abnormalities in any bone tissues.
- the present inventors have made earnest studies to find out a promoting factor for bone formation using a cultural assay and finally completed this invention.
- Integ ⁇ n may participate m the interaction between cells and cells or between cells and extracellular matrices and play an important role in wound healing, development, immunization, he ostasis or metastasis.
- Integrin superfamily s an oi,0-heterod ⁇ mer group found on the cell surface and may combine extracellular ligancs and cytoskeleton. All integ- rins are heterodimers and each sub-unit is extracellular by 90% and may have a long membrane permeable domain and a short mtracellular domain. The extracellular domain is bound with the extracellular matrices or ligands of the cell surface, while the mtracellular ⁇ omain is bound with cytoskeleton proteins.
- Bone matrices such as osteopontin, bone sialoglycoproteins, thrombospondin, fibronectin and vitronectm are found in bone and all proteins have been found to have the RGD sequence. Recently, osteoclasts have been found to have integrin ⁇ .V/33 and a2 ⁇ l in the cell membrane surface (Davies J. et al. , J. Cell Biol. , Vol.l,
- echstatin a protein derived from snake venom and having the RGD sequence and a platelet aggregation inhibiting activity
- a synthetic GdRGDSP peptide and a cyclic synthetic GPenGRGDSPCA peptide can inhibit bone absorption by mouse osteoclasts and GdRGDSP peptide can inhibit the formation of tartaric acid-resistant and phosphatase-positive multinuclear osteoclasts (Gabri V. D. P. et al. , J. Bone Miner. Res., Vol.9, p.1021, 1994), it is suggested that recognition and adhesion of bone matrices by integrin and related cytoskeleton does deeply participate in the development of bone absorption function of osteoclasts.
- the adhesion of cell matrices between osteoblasts and bone matrices would be caused by the adhesion mechanism via collagen and fibronectin in the bone matrices and ⁇ l integrin of osteoblasts.
- the cell adhesion of osteoblasts with osteoclasts can be performed via fibronectin as both ⁇ 3 integrin of osteoclasts and ⁇ l integrin in osteoblasts may be a receptor for fibronectin.
- the disintegrin family including echstatin or kistrin (William R. G. et al.
- Bone formation can be promoted by administering a peptide or polypeptide containing the RGD sequence in the molecule or a biologically acceptable salt thereof to pa ⁇ tients.
- the peptides or polypeptide containing the RGD se ⁇ quence in the molecule may illustratively include kistrin, echstatin, a peptide represented by Gly-Arg-Gly-Asp-Ser (hereinafter referred to as GRGDS) , a compound represented by the general formula (I)
- R 1( R 2 , 3, R 4 , 5 and Rg may be the same or diffe ⁇ rent and each represents one selected from the group consisting of a hydrogen atom; an alkyl group of 1-8 carbon atoms optionally substituted with one selected from the group consisting of a hydroxy group, a carboxy group, a cycloalkyl group of 3-10 carbon atoms optionally substituted with a hydroxy group, and an aryl group of 6-12 carbon atoms optio ⁇ nally substituted with a hydroxy group ; a cycloalkyl group of 3-10 carbon atoms optionally substituted with hydroxy group and an aryl group of 6-12 carbon atoms optionally subs ⁇ tituted with a hydroxy group, R7 and R8 may be the same of different and each represents a group selected from the group consisting of a hydroxy group, an alkoxy group of 1-8 carbon atoms, an alkenyloxy group of 2-12 carbon atoms, a cyclo
- R 14 and R 15 may be the same or different and each represents a group selected from the group consisting of a hydroxy group, an alkoxy group of 1-8 carbon atoms, an alkenyloxy group of 2-12 carbon atoms, a cycloalkyloxy group of 3-10 carbon atoms and an aryloxy group of 6-12 carbon atoms
- X represents S or SO.
- this invention provides a new compound represented by the formula (II) . Also, this invention is directed to a therapeutic method for promoting bone formation which comprises administering to patients a compound represented by the general formula (IX)
- R 17 represents a hydrogen atom or an alkyl group of 1-4 carbon atoms optionally substituted with a phenyl group
- R 18 represents a hydrogen atom, an alkyl group of 1-4 carbon atoms, a phenyl group optionally substituted with a methoxy group or -COR 21 (in which R 21 represents -OH, -NH 2 , -NH- (CH 2 ) 2 -phenyl, an alkoxy group of 1-3 carbon atoms, a benzyloxy group, Pro or Aoc)
- R 19 represents an alkyl group of 1-5 carbon atoms
- Kistrin and echstatin are proteins having molecular weights of about 7,300 and about 5,400, respectively, and they are disclosed, for instance, Protein Science (1993) , 2, 1749- 1755.
- the GRGDS may be easily synthesized according to a conventional peptide synthesis.
- the compounds of the general formula (I) are disclosed m U.S. Patent No. 5,384,3- 09 and their representative compounds may be illustrated by the formulae (III) - (VI) .
- the compounds of the general formula (II) are novel and may be prepared according to the method as described in
- the compounds of the general formulae (IX) , (X) , (XI) and (XII) are known and may be synthesized according to the methods disclosed in EP-A0499079, EP-A0530505, EP- A0566919, WO 95/14008, EP-A0528586 and WO 93/19046.
- a daily dose of 0.001 - 10 mg/kg body weight preferably 0.01 - 1 mg/kg body weight
- a daily dose of 0.001 - 10 mg/kg body weight preferably 0.01 - 1 mg/kg body weight, is used.
- the present drug may be systemically administered by intravenous injection, intramuscular injection, intraperitoneal injection, oral administration, parenteral administration such as suppository or any other prior art means.
- pharmaceutical preparations there may be intended injectable or oral pharmaceutical preparations.
- injectable pharmaceutical preparations may include, for example, injectable powders.
- suitable water-soluble excipients such as mannitol, sucrose, maltose, glucose and fructose may be added and dissolved in water and the solution is poured portionwise into ampoules and freeze-dried and sealed to form pharmaceutical preparations.
- Oral pharmaceutical preparations may include conventional tablets, capsules, granules, fine granules, powders as well as enteric coated preparations.
- a carrier containing the present drug may be more preferably implanted in the area close to the fractured portion.
- natural polymeric substances such as collagen or fibrin glue, synthetic polymeric substances capable of being dispersed in living body such as poly lactated glycolic acid can be used for carriers.
- the present agent may be applied by coating on the surface of the bone or tooth to be transplanted with an adhesive substance such as collagen paste or fibrin glue. And, it may be applied to the tissue, the bone or alveolar bone in the portion to which bone or tooth is to be transplanted.
- artificial bone or artificial fang may be used which is composed of, for example, metals, ceramics, glass and other natural or artificial inorganic substances such as hydroxyapatite.
- the surface of artificial bone composed of a denser materials is roughened to keep the present agent over the said surface.
- the Compounds GH 4 and GH 5 were prepared according to the standard FMOC method as described in P.L. Barker et al., J.Med.Chem. , 35, p. 2040-2048, 1992.
- FMOC-S-trityl-cysteine bound to Wang resin was used as a starting material and the FMOC amino acid having a suitable side chain protecting group, D-aspartic acid(0-t-butyl) ; L-aspartic acid(O- -butyl) ; glycine; L-arginine(N-2,2,5, 7,8-pentarae- thylchromane-6-sulfonyl) were in turn used in 3 moles portions.
- the FMOC at the N- erminal was removed with piperidine (in the form of a 20% solution in dimethyl- acetamide) and racemic 2-bromo-2-phenylacetic acid (4 equivalents) activated with diisopropylcarb ⁇ diimide (2 equivalents) was added to the free N-terminal.
- the S-trityl group at the cysteine side chain was removed with a chloro- methane solution containing dilute trifluoroacetic acid (2%) and then the resulting peptide was cyclized by addition of a solution of diisopropylethylamine (2 equivalents) in dimethylacetamide.
- echstatin 10 ⁇ g was dissolved in 1 ml of water and a water soluble excipient, sucrose, was added so as to be at 1.25 - 40 w/v% . It was sterilely filtered by means of a 0.22 ⁇ m filter (available from Milipore Inc.) . It was added in portions to vessels, freeze-dried and sealed to form prepara ⁇ tions.
- Calvaria was excised from rat fetus of 20 days old and osteoblast-like cells were prepared by enzymatic treatment.
- the osteoblast-like cells were incubated in MEMo_(+) medium containing 100 ⁇ l/ml ascorbic acid, 2mM /5-glycerol phosphate and 10% bovine fetal serum to form bone tuberculum.
- MEMo_(+) medium containing 100 ⁇ l/ml ascorbic acid, 2mM /5-glycerol phosphate and 10% bovine fetal serum to form bone tuberculum.
- kistrin and echstatin did promote calcification and the number of bone tuberculum at 10 "7 and 10 ⁇ 8 M. Promoted alkaline phosphatase activity was observed at 10 "8 M.
- Fetuses of 20 days old were taken out from pregnant rat and immersed in 70% ethanol. Calvaria was exposed by removing scalp using nose-bent forceps and nose-bent scissors. Calvaria was cut out without removing periosteum and immersed in a bovine fetal serum-free medium. Connective tissues traveling toward front and rear in the central area and surrounding soft tissues were cut off using a scalpel. All bone pieces thus prepared were placed into a 50 ml centrifugal tube. 10 ml of the enzyme solution was added and the tube was shaken in a thermostat at 37°C for 5 minutes.
- Fraction 1 The treated liquid with dispersed cells was recovered and centrifuged at 1200 rpm for 5 minutes followed by removing a supernatant. 15 ml of F12 , 10% FCS medium was added and cells were untied well and then spread on a 10 cm petri dish, which was defined as Fraction 1. To the bone pieces after recovering the treated liquid of the Fraction 1 was added 10 ml of the enzyme solution and shaken in a thermostat at 37°C for 10 minutes. After centrifugation, the resulting cells were defined as Fraction 2.
- the cells in those fractions up to Fraction 5 were obtained in the similar enzyme treatment as above and the cells of Fractions 3-5 were incubated in a carbon dioxide incubator for 2 - 3 days using F12 medium containing 10% bovine fetal serum. After incubation, the cells were recovered by treating with 0.25% trypsin (EDTAfree) . After counting the number of cells, cells were noculated to a 4-well incubation plate (Nunc) at 1900 cells/300 ⁇ l (1000 cells/cm 2 ) and incubation was continued for a further 2 - 3 days. After incubation, all cultured liquid was removed, 300 ⁇ l of the medium containing the active compound or dexamethasone
- the eluent 1% Triton X-100, 0.5 mM magnesium chloride, 10 mM Tris, pH 7.2
- Alkaline phosphatase activity ( ⁇ mole/min/well) +
- the compounds of the formula (IV) , GH 4, GH 5 and the formula (V) did promote calcification and the number of bone tuberculum at 10 " ⁇ and 10 "8 M.
- the compounds of the formula (III) , GH 4, GH 5 and the formula (V) did completely prevent calcification at 10 M, but were not observed to affect the number of bone tuberculum.
- the compound of the formula (III) did promote calcification at 10 " 8 and 10 "10 M and did promote the number of bone tuberculum at 10 ⁇ 6 M.
- the GRGDS did promote calcification at 10 "6 M, but did completely prevent calcification at 10 "4 M.
- the number of bone tuberculum was observed to show a tendency to be increased at these concentrations.
- Kistrin and Compound No. 43 were tested using the bone tuberculum formation test as described above. The results are shown in Table 3.
- An agent for promoting bone formation which comprises as an active ingredient a peptide or polypeptide having the amino acid sequence composed of ArgGlyAsp in the molecule such as kistrin, echstatin, a peptide represented by Gly-Arg- Gly-Asp-Ser, a compound of the above formula (I) or (II) , or a compound of the formula (IX) , (X) , (XI) or (XII) , can be administered to human body or implanted into the area close to the fractured bone to accomplish effective prophylaxis and therapy of bone fracture.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Biomedical Technology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Marine Sciences & Fisheries (AREA)
- Hematology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Rehabilitation Tools (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IL12462396A IL124623A0 (en) | 1995-12-08 | 1996-12-06 | Agents for promoting bone formation |
JP9521692A JP2000502996A (en) | 1995-12-08 | 1996-12-06 | Bone formation promoter |
EP96942315A EP0865446B1 (en) | 1995-12-08 | 1996-12-06 | Agents for promoting bone formation |
DE69636987T DE69636987T2 (en) | 1995-12-08 | 1996-12-06 | MEANS FOR PROMOTING BONE TRAINING |
US09/077,714 US6194380B1 (en) | 1995-12-08 | 1996-12-06 | Agents for promoting bone formation |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP34505795A JP3895792B2 (en) | 1995-12-08 | 1995-12-08 | Bone formation promoter |
JP7/345057 | 1995-12-08 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/626,302 Division US6344439B1 (en) | 1995-12-08 | 2000-07-26 | Agents for promoting bone formation |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997021726A1 true WO1997021726A1 (en) | 1997-06-19 |
Family
ID=18374002
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1996/005380 WO1997021726A1 (en) | 1995-12-08 | 1996-12-06 | Agents for promoting bone formation |
Country Status (8)
Country | Link |
---|---|
US (2) | US6194380B1 (en) |
EP (1) | EP0865446B1 (en) |
JP (2) | JP3895792B2 (en) |
AT (1) | ATE357456T1 (en) |
CA (1) | CA2236335A1 (en) |
DE (1) | DE69636987T2 (en) |
IL (1) | IL124623A0 (en) |
WO (1) | WO1997021726A1 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999032457A1 (en) * | 1997-12-19 | 1999-07-01 | Aventis Pharma Deutschland Gmbh | Novel acylguanidine derivatives as inhibitors of bone resorption and as vitronectin receptor antagonists |
WO1999037621A1 (en) * | 1998-01-23 | 1999-07-29 | Aventis Pharma Deutschland Gmbh | Novel sulfonamide derivatives as inhibitors of bone resorption and as inhibitors of cell adhesion |
FR2786182A1 (en) * | 1998-11-24 | 2000-05-26 | Hoechst Marion Roussel Inc | Acylguanidine derivatives, useful for prevention and treatment of e.g. restenosis, arteriosclerosis, nephropathias, are victronectin receptor antagonists, cellular adhesion inhibitors, and inhibitors of osteoclast bone resorption |
US6090944A (en) * | 1998-08-13 | 2000-07-18 | Merck & Co., Inc. | Alkanoic acid derivatives as αv integrin receptor antagonists |
EP1108721A1 (en) * | 1999-12-15 | 2001-06-20 | Aventis Pharma Deutschland GmbH | Thienylalanine derivatives as inhibitors of cell adhesion |
WO2001074180A1 (en) * | 2000-01-20 | 2001-10-11 | Osteoscreen, Inc. | Nutritional supplements for stimulating bone growth |
US6313119B1 (en) | 1998-01-23 | 2001-11-06 | Adventis Pharma Deutschland Gmbh | Sulfonamide derivatives as inhibitors of bone resorption and as inhibitors of cell adhesion |
US6410521B1 (en) | 1998-06-12 | 2002-06-25 | Osteoscreen, Inc. | Nutritional supplements for stimulating bone growth |
WO2008126974A1 (en) * | 2007-04-16 | 2008-10-23 | Biorunx Co., Ltd. | Composition for preventing and treating osseous metabolic disease |
EP3312191A4 (en) * | 2015-06-18 | 2019-03-13 | Seoul National University R&DB Foundation | Peptide for promoting osteogenesis or inhibiting osteolysis, and use thereof |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3895792B2 (en) * | 1995-12-08 | 2007-03-22 | プロスケリア・エス・ア・エス | Bone formation promoter |
EP0796855B1 (en) * | 1996-03-20 | 2002-02-06 | Hoechst Aktiengesellschaft | Inhibitors of bone resorption and vitronectin receptor antagonists |
BR0309877A (en) | 2002-05-03 | 2005-04-26 | Millenium Biologix Inc | Connective tissue stimulating peptides |
US7399826B1 (en) | 2003-10-02 | 2008-07-15 | Ali Sadat M | Peptide for promoting healing of fractures |
KR101013999B1 (en) * | 2004-03-19 | 2011-02-14 | 재단법인서울대학교산학협력재단 | Membrane and implant immobilized osteogenic enhancing peptides on the surface |
KR100676945B1 (en) * | 2005-03-18 | 2007-02-01 | 재단법인서울대학교산학협력재단 | Bone graft and scaffolding materials immobilized with osteogenesis enhancing peptides on the surface |
KR100757241B1 (en) * | 2006-09-13 | 2007-09-10 | 재단법인서울대학교산학협력재단 | Bone graft containing osteogenesis enhancing peptides |
KR100879704B1 (en) * | 2008-06-11 | 2009-01-22 | 오스템임플란트 주식회사 | Oligopeptide for enhancing osteointegration and bone formation |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0528586A1 (en) * | 1991-08-09 | 1993-02-24 | Merck & Co. Inc. | Inhibiting osteoclast-mediated bone resorption using aminoalkyl-substituted phenyl derivatives |
EP0530505A2 (en) * | 1991-08-08 | 1993-03-10 | Hoechst Aktiengesellschaft | Hydantoin derivatives |
US5384309A (en) * | 1989-07-17 | 1995-01-24 | Genentech, Inc. | Cyclized peptides and their use as platelet aggregation inhibitors |
WO1995014008A1 (en) * | 1993-11-15 | 1995-05-26 | Hoechst Aktiengesellschaft | Substituted 5-ring heterocycles, their preparation and their use |
WO1996000240A1 (en) * | 1994-06-27 | 1996-01-04 | Snow Brand Milk Products Co., Ltd. | Novel protein and process for producing the same |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3895792B2 (en) * | 1995-12-08 | 2007-03-22 | プロスケリア・エス・ア・エス | Bone formation promoter |
-
1995
- 1995-12-08 JP JP34505795A patent/JP3895792B2/en not_active Expired - Lifetime
-
1996
- 1996-12-06 EP EP96942315A patent/EP0865446B1/en not_active Expired - Lifetime
- 1996-12-06 US US09/077,714 patent/US6194380B1/en not_active Expired - Lifetime
- 1996-12-06 IL IL12462396A patent/IL124623A0/en unknown
- 1996-12-06 AT AT96942315T patent/ATE357456T1/en not_active IP Right Cessation
- 1996-12-06 DE DE69636987T patent/DE69636987T2/en not_active Expired - Lifetime
- 1996-12-06 WO PCT/EP1996/005380 patent/WO1997021726A1/en active IP Right Grant
- 1996-12-06 CA CA002236335A patent/CA2236335A1/en not_active Abandoned
- 1996-12-06 JP JP9521692A patent/JP2000502996A/en active Pending
-
2000
- 2000-07-26 US US09/626,302 patent/US6344439B1/en not_active Expired - Lifetime
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5384309A (en) * | 1989-07-17 | 1995-01-24 | Genentech, Inc. | Cyclized peptides and their use as platelet aggregation inhibitors |
EP0530505A2 (en) * | 1991-08-08 | 1993-03-10 | Hoechst Aktiengesellschaft | Hydantoin derivatives |
EP0528586A1 (en) * | 1991-08-09 | 1993-02-24 | Merck & Co. Inc. | Inhibiting osteoclast-mediated bone resorption using aminoalkyl-substituted phenyl derivatives |
WO1995014008A1 (en) * | 1993-11-15 | 1995-05-26 | Hoechst Aktiengesellschaft | Substituted 5-ring heterocycles, their preparation and their use |
WO1996000240A1 (en) * | 1994-06-27 | 1996-01-04 | Snow Brand Milk Products Co., Ltd. | Novel protein and process for producing the same |
Non-Patent Citations (7)
Title |
---|
BARKER P.L. ET AL.: "Cyclic RGD Peptide Analogues as Antiplatelet Antithrombotics", J.MED.CHEM., vol. 35, - 1992, pages 2040 - 2048, XP002029505 * |
DRESDNER-POLLAK: "Blockade of Osteoclast-Mediated Bone Resorption through Occupancy of the Integrin Receptor: A potential Approach th the Therapy of Osteoporosis", J.CELLULAR BIOCHEM., vol. 56, 1994, pages 323 - 330, XP000652575 * |
FISHER J.E. ET AL.: "Inhibition of osteoclastic bone resorbtion in vivio by echistatin, an "Arginyl-Glycyl-Aspartyl" (RGD)-containing protein", ENDOCRINOLOGY, vol. 132, no. 3, 1993, BALTIMORE, pages 1411 - 1413, XP000652599 * |
HORTON M.A. ET AL.: "Arg-Gly-Asp (RGD) Peptides and the Anti-Vironectin Receptor Antibody 23C6 inhibit Dentine Resorption and Cell Spreading by Osteoclasts", EXPERIMENTAL CELL RESEARCH, vol. 195, 1991, pages 368 - 375, XP000651755 * |
KING K.L. ET AL: "Effects of Kistrin on Bone Resorption in vitro and Serum Calcium in vivo", J.BONE AND MINERAL RES., vol. 9, no. 3, 1994, pages 381387, XP000653332 * |
OURSLER M.J. AND TH.C. SPELSBERG: "Editoral: Echistatin, A Potential New Drug for Osteoporosis", ENDOCRINOLOGY, vol. 132, no. 3, 1993, BALTIMORE, pages 939 - 940, XP000652637 * |
VAN DER PLUIJM G. ET AL.: "Integrins and Osteoclastic Resorbtion in Three Bone Organ Cultures: Differential Sensitivitiy to Synthetic Arg-Gly-Asp Peptides during Osteoclast Formation", J. BONE AND MINERAL RES., vol. 9, no. 7, 1994, pages 1021 - 1028, XP000651794 * |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0933367A1 (en) * | 1997-12-19 | 1999-08-04 | Hoechst Marion Roussel Deutschland GmbH | Novel acylguanidine derivates as inhibitors of bone resorption and as vitronectin receptor antagonists |
WO1999032457A1 (en) * | 1997-12-19 | 1999-07-01 | Aventis Pharma Deutschland Gmbh | Novel acylguanidine derivatives as inhibitors of bone resorption and as vitronectin receptor antagonists |
US6492356B1 (en) | 1997-12-19 | 2002-12-10 | Aventis Pharma Deutschland Gmbh | Acylguanidine derivatives as inhibitors of bone resorption and as vitronectin receptor antagonists |
US6313119B1 (en) | 1998-01-23 | 2001-11-06 | Adventis Pharma Deutschland Gmbh | Sulfonamide derivatives as inhibitors of bone resorption and as inhibitors of cell adhesion |
WO1999037621A1 (en) * | 1998-01-23 | 1999-07-29 | Aventis Pharma Deutschland Gmbh | Novel sulfonamide derivatives as inhibitors of bone resorption and as inhibitors of cell adhesion |
US6747148B2 (en) | 1998-01-23 | 2004-06-08 | Hoechst Marion Roussel Deutschland Gmbh | Sulfonamide derivatives as inhibitors of bone resorption and as inhibitors of cell adhesion |
AP1269A (en) * | 1998-01-23 | 2004-04-03 | Aventis Pharma Deutschland Gmbh | Novel salfonamide derivatives as inhibitors of bone resorption and as inhibitors of cell adhesion. |
US6410521B1 (en) | 1998-06-12 | 2002-06-25 | Osteoscreen, Inc. | Nutritional supplements for stimulating bone growth |
US6090944A (en) * | 1998-08-13 | 2000-07-18 | Merck & Co., Inc. | Alkanoic acid derivatives as αv integrin receptor antagonists |
US6602878B1 (en) | 1998-11-24 | 2003-08-05 | Aventis Pharma S.A. | Acylquanidine derivatives, method for preparing same, application as medicines and pharmaceutical compositions containing them |
WO2000031046A1 (en) * | 1998-11-24 | 2000-06-02 | Aventis Pharma S.A. | Novel acylguanidine derivatives, method for preparing same, application as medicines and pharmaceutical compositions containing them |
FR2786182A1 (en) * | 1998-11-24 | 2000-05-26 | Hoechst Marion Roussel Inc | Acylguanidine derivatives, useful for prevention and treatment of e.g. restenosis, arteriosclerosis, nephropathias, are victronectin receptor antagonists, cellular adhesion inhibitors, and inhibitors of osteoclast bone resorption |
WO2001044237A1 (en) * | 1999-12-15 | 2001-06-21 | Aventis Pharma Deutschland Gmbh | Thienylalanine derivatives as inhibitors of cell adhesion |
EP1108721A1 (en) * | 1999-12-15 | 2001-06-20 | Aventis Pharma Deutschland GmbH | Thienylalanine derivatives as inhibitors of cell adhesion |
US6762190B2 (en) | 1999-12-15 | 2004-07-13 | Aventis Pharma S.A. Deutschland Gmbh Genentech, Inc. | Thienylalanine derivatives as inhibitors of cell adhesion |
WO2001074180A1 (en) * | 2000-01-20 | 2001-10-11 | Osteoscreen, Inc. | Nutritional supplements for stimulating bone growth |
WO2008126974A1 (en) * | 2007-04-16 | 2008-10-23 | Biorunx Co., Ltd. | Composition for preventing and treating osseous metabolic disease |
EP3312191A4 (en) * | 2015-06-18 | 2019-03-13 | Seoul National University R&DB Foundation | Peptide for promoting osteogenesis or inhibiting osteolysis, and use thereof |
Also Published As
Publication number | Publication date |
---|---|
CA2236335A1 (en) | 1997-06-19 |
IL124623A0 (en) | 1998-12-06 |
JP2000502996A (en) | 2000-03-14 |
EP0865446B1 (en) | 2007-03-21 |
EP0865446A1 (en) | 1998-09-23 |
DE69636987T2 (en) | 2007-12-06 |
US6194380B1 (en) | 2001-02-27 |
JP3895792B2 (en) | 2007-03-22 |
US6344439B1 (en) | 2002-02-05 |
DE69636987D1 (en) | 2007-05-03 |
ATE357456T1 (en) | 2007-04-15 |
JPH09157181A (en) | 1997-06-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6344439B1 (en) | Agents for promoting bone formation | |
EP0617705B1 (en) | Non-peptidic surrogates of the arg-gly-asp sequence and pharmaceutical compositions comprising them | |
JP2735298B2 (en) | Novel platelet aggregation inhibitor | |
US5958428A (en) | Synthetic compounds and compositions with enhanced cell binding | |
EP0502926B1 (en) | Anti-thrombotic peptides and pseudopeptides | |
AU639409B2 (en) | Conformationally stabilized cell adhesion peptides | |
JP3054150B2 (en) | Polypeptides, compositions and methods of use derived from thrombin | |
JP3200609B2 (en) | Epithelial cell growth promoter | |
JPH05504336A (en) | Peptide derivatives, their production methods, pharmaceuticals containing them, and methods for treating glaucoma | |
JP2010155859A (en) | Bioactive keratin protein | |
EP1017382A1 (en) | Biarylalkanoic acids as cell adhesion inhibitors | |
WO1991005562A1 (en) | Anti-thrombotic peptides and pseudopeptides | |
US5231082A (en) | Cyclic peptide with anti-metastasis activity | |
KR100993233B1 (en) | Novel peptides and medicinal uses thereof | |
EP0397635B1 (en) | Peptide with anti-metastasis activity | |
EP0812205B1 (en) | Antithrombotic azacycloalkylalkanoyl peptides and pseudopeptides | |
JP2002509895A (en) | Use of an isolated domain of type IV collagen to modify cell and tissue interactions | |
MXPA98004449A (en) | Agents to promote training or | |
JPH10259134A (en) | Wound healing promoter | |
JP2013518917A (en) | Novel aminoalkyloxazoles and aminoalkylthiazolecarboxylic amides as regeneration promoters for sensory organs and postmitotic tissues | |
CN1413251A (en) | Novel endoplasmic reticulum-localized protein, remedies containing the same for diseases associated with glycoprotein abnormality, DNA encoding this protein and gene remedies containing the same | |
JPH0551400A (en) | Short chain collagen | |
JP2617700B2 (en) | Polypeptide consisting of repeating structure of cell adhesion active core sequence | |
AU636427C (en) | Peptide derivative, process for the preparation thereof, pharmaceutical preparation containing it and method for treatment of glaucoma | |
IL100130A (en) | Guanidine derivatives and pharmaceutical compositions comprising them |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): CA IL JP MX US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2236335 Country of ref document: CA Ref country code: CA Ref document number: 2236335 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1996942315 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/1998/004449 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 1997 521692 Kind code of ref document: A Format of ref document f/p: F |
|
WWP | Wipo information: published in national office |
Ref document number: 1996942315 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09077714 Country of ref document: US |
|
WWG | Wipo information: grant in national office |
Ref document number: 1996942315 Country of ref document: EP |