JP5200027B2 - Pth受容体モジュレーターとしてのペグ化pthおよびその使用 - Google Patents
Pth受容体モジュレーターとしてのペグ化pthおよびその使用 Download PDFInfo
- Publication number
- JP5200027B2 JP5200027B2 JP2009532504A JP2009532504A JP5200027B2 JP 5200027 B2 JP5200027 B2 JP 5200027B2 JP 2009532504 A JP2009532504 A JP 2009532504A JP 2009532504 A JP2009532504 A JP 2009532504A JP 5200027 B2 JP5200027 B2 JP 5200027B2
- Authority
- JP
- Japan
- Prior art keywords
- daltons
- bone
- seq
- mpeg
- leu
- 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.)
- Expired - Fee Related
Links
- 108090000445 Parathyroid hormone Proteins 0.000 title description 29
- 229940075993 receptor modulator Drugs 0.000 title 1
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 24
- 241000124008 Mammalia Species 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims description 109
- 210000000988 bone and bone Anatomy 0.000 claims description 56
- 150000003839 salts Chemical class 0.000 claims description 32
- 229920001223 polyethylene glycol Polymers 0.000 claims description 29
- 239000002202 Polyethylene glycol Substances 0.000 claims description 24
- 206010017076 Fracture Diseases 0.000 claims description 17
- 230000001965 increasing effect Effects 0.000 claims description 13
- 230000011164 ossification Effects 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 239000007943 implant Substances 0.000 claims description 10
- 208000029725 Metabolic bone disease Diseases 0.000 claims description 8
- 206010049088 Osteopenia Diseases 0.000 claims description 8
- 229920001427 mPEG Polymers 0.000 claims description 6
- 239000004053 dental implant Substances 0.000 claims description 5
- 208000028169 periodontal disease Diseases 0.000 claims description 5
- 230000009286 beneficial effect Effects 0.000 claims description 4
- 230000004927 fusion Effects 0.000 claims description 3
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 25
- 238000011282 treatment Methods 0.000 abstract description 20
- 206010065687 Bone loss Diseases 0.000 abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
- 230000002265 prevention Effects 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 44
- 239000003981 vehicle Substances 0.000 description 34
- 238000003556 assay Methods 0.000 description 20
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 description 20
- 241000700159 Rattus Species 0.000 description 18
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- 239000000203 mixture Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 102000003982 Parathyroid hormone Human genes 0.000 description 15
- 239000000199 parathyroid hormone Substances 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- 208000037147 Hypercalcaemia Diseases 0.000 description 13
- 230000000148 hypercalcaemia Effects 0.000 description 13
- 208000030915 hypercalcemia disease Diseases 0.000 description 13
- 210000002966 serum Anatomy 0.000 description 13
- DYFJZDDQPNIPAB-NHCYSSNCSA-N Glu-Arg-Val Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(O)=O DYFJZDDQPNIPAB-NHCYSSNCSA-N 0.000 description 12
- WVYJNPCWJYBHJG-YVNDNENWSA-N Glu-Ile-Gln Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(O)=O WVYJNPCWJYBHJG-YVNDNENWSA-N 0.000 description 12
- HGJREIGJLUQBTJ-SZMVWBNQSA-N Glu-Trp-Leu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CC(C)C)C(O)=O HGJREIGJLUQBTJ-SZMVWBNQSA-N 0.000 description 12
- 102100036893 Parathyroid hormone Human genes 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 239000011575 calcium Substances 0.000 description 12
- 229910052791 calcium Inorganic materials 0.000 description 12
- 230000000121 hypercalcemic effect Effects 0.000 description 12
- 208000010392 Bone Fractures Diseases 0.000 description 11
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 9
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 9
- 229940095074 cyclic amp Drugs 0.000 description 9
- 229910052500 inorganic mineral Inorganic materials 0.000 description 9
- 239000011707 mineral Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- JPXNYFOHTHSREU-UWVGGRQHSA-N Gly-Arg-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CN JPXNYFOHTHSREU-UWVGGRQHSA-N 0.000 description 8
- BQSLGJHIAGOZCD-CIUDSAMLSA-N Leu-Ala-Ser Chemical compound CC(C)C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(O)=O BQSLGJHIAGOZCD-CIUDSAMLSA-N 0.000 description 8
- JGUWRQWULDWNCM-FXQIFTODSA-N Ser-Val-Ser Chemical compound [H]N[C@@H](CO)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O JGUWRQWULDWNCM-FXQIFTODSA-N 0.000 description 8
- 210000002436 femur neck Anatomy 0.000 description 8
- 108010025306 histidylleucine Proteins 0.000 description 8
- 125000005647 linker group Chemical group 0.000 description 8
- ZCVBHUKHCDVNRY-ZLELNMGESA-N (2s)-2-aminohexanoic acid;(2s)-2-amino-4-methylpentanoic acid Chemical compound CCCC[C@H](N)C(O)=O.CC(C)C[C@H](N)C(O)=O ZCVBHUKHCDVNRY-ZLELNMGESA-N 0.000 description 7
- JNDYEOUZBLOVOF-AVGNSLFASA-N Leu-Leu-Gln Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O JNDYEOUZBLOVOF-AVGNSLFASA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 210000004899 c-terminal region Anatomy 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 229920005989 resin Polymers 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- 238000004007 reversed phase HPLC Methods 0.000 description 7
- 210000000689 upper leg Anatomy 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XQFLFQWOBXPMHW-NHCYSSNCSA-N Asp-Val-His Chemical compound N[C@@H](CC(=O)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC1=CNC=N1)C(=O)O XQFLFQWOBXPMHW-NHCYSSNCSA-N 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 230000001747 exhibiting effect Effects 0.000 description 6
- 230000001939 inductive effect Effects 0.000 description 6
- 108010073230 parathyroid hormone (1-38) Proteins 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 206010041569 spinal fracture Diseases 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- OMCKWYSDUQBYCN-FXQIFTODSA-N Ala-Ser-Met Chemical compound [H]N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(O)=O OMCKWYSDUQBYCN-FXQIFTODSA-N 0.000 description 5
- NVCIXQYNWYTLDO-IHRRRGAJSA-N Arg-His-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CN=CN1)NC(=O)[C@H](CCCN=C(N)N)N NVCIXQYNWYTLDO-IHRRRGAJSA-N 0.000 description 5
- WIDVAWAQBRAKTI-YUMQZZPRSA-N Asn-Leu-Gly Chemical compound [H]N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(O)=O WIDVAWAQBRAKTI-YUMQZZPRSA-N 0.000 description 5
- POMXSEDNUXYPGK-IHRRRGAJSA-N Leu-Met-His Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC1=CN=CN1)C(=O)O)N POMXSEDNUXYPGK-IHRRRGAJSA-N 0.000 description 5
- 125000003275 alpha amino acid group Chemical group 0.000 description 5
- 238000009739 binding Methods 0.000 description 5
- 230000037118 bone strength Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000021615 conjugation Effects 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 4
- CLICCYPMVFGUOF-IHRRRGAJSA-N Arg-Lys-Leu Chemical compound [H]N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(O)=O CLICCYPMVFGUOF-IHRRRGAJSA-N 0.000 description 4
- JWTKVPMQCCRPQY-SRVKXCTJSA-N His-Asn-Leu Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(O)=O JWTKVPMQCCRPQY-SRVKXCTJSA-N 0.000 description 4
- LIEIYPBMQJLASB-SRVKXCTJSA-N His-Gln-Arg Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC1=CN=CN1 LIEIYPBMQJLASB-SRVKXCTJSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- FIODMZKLZFLYQP-GUBZILKMSA-N Pro-Val-Ser Chemical compound [H]N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CO)C(O)=O FIODMZKLZFLYQP-GUBZILKMSA-N 0.000 description 4
- 238000012754 cardiac puncture Methods 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000002224 dissection Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 108010050848 glycylleucine Proteins 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 210000000614 rib Anatomy 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- -1 2-chlorotrityl Chemical group 0.000 description 3
- 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 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 108010049264 Teriparatide Proteins 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000037176 bone building Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000000099 in vitro assay Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 210000004705 lumbosacral region Anatomy 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000010254 subcutaneous injection Methods 0.000 description 3
- 239000007929 subcutaneous injection Substances 0.000 description 3
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 229940122361 Bisphosphonate Drugs 0.000 description 2
- 0 CC([C@@](CCCCNC(C*)O)NC)O Chemical compound CC([C@@](CCCCNC(C*)O)NC)O 0.000 description 2
- 102000055006 Calcitonin Human genes 0.000 description 2
- 108060001064 Calcitonin Proteins 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- 102000006461 Parathyroid Hormone Receptors Human genes 0.000 description 2
- 108010058828 Parathyroid Hormone Receptors Proteins 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 102000030621 adenylate cyclase Human genes 0.000 description 2
- 108060000200 adenylate cyclase Proteins 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 210000003423 ankle Anatomy 0.000 description 2
- 210000000617 arm Anatomy 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 150000004663 bisphosphonates Chemical class 0.000 description 2
- 230000035563 calcemia Effects 0.000 description 2
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 2
- 229960004015 calcitonin Drugs 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 150000003857 carboxamides Chemical class 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- 210000000245 forearm Anatomy 0.000 description 2
- 229940053641 forteo Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000009806 oophorectomy Methods 0.000 description 2
- 210000000963 osteoblast Anatomy 0.000 description 2
- 230000001009 osteoporotic effect Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 210000004197 pelvis Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000008196 pharmacological composition Substances 0.000 description 2
- 229920005990 polystyrene resin Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 210000004872 soft tissue Anatomy 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- 238000013223 sprague-dawley female rat Methods 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000002303 tibia Anatomy 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- DYWUPCCKOVTCFZ-LBPRGKRZSA-N (2s)-2-amino-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)C=C(C[C@H](N)C(O)=O)C2=C1 DYWUPCCKOVTCFZ-LBPRGKRZSA-N 0.000 description 1
- GVIXTVCDNCXXSH-AWEZNQCLSA-N (2s)-2-amino-5-[[amino-[(2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)sulfonylamino]methylidene]amino]pentanoic acid Chemical compound OC(=O)[C@@H](N)CCCN=C(N)NS(=O)(=O)C1=C(C)C(C)=C2OC(C)(C)CC2=C1C GVIXTVCDNCXXSH-AWEZNQCLSA-N 0.000 description 1
- VVQIIIAZJXTLRE-QMMMGPOBSA-N (2s)-2-amino-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound CC(C)(C)OC(=O)NCCCC[C@H](N)C(O)=O VVQIIIAZJXTLRE-QMMMGPOBSA-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
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- FZTIWOBQQYPTCJ-UHFFFAOYSA-N 4-[4-(4-carboxyphenyl)phenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1C1=CC=C(C=2C=CC(=CC=2)C(O)=O)C=C1 FZTIWOBQQYPTCJ-UHFFFAOYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- UOELMDIOCSFSEN-FVZZCGLESA-N 7-Dehydrositosterol Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)C=C[C@H](C)C(C)C)=CC=C1C[C@@H](O)CCC1=C.C1[C@@H](O)CCC2(C)C(CC[C@@]3([C@@H]([C@H](C)C=C[C@H](C)C(C)C)CC[C@H]33)C)C3=CC=C21 UOELMDIOCSFSEN-FVZZCGLESA-N 0.000 description 1
- ZZOKVYOCRSMTSS-UHFFFAOYSA-M 9h-fluoren-9-ylmethoxymethanimidate Chemical compound C1=CC=C2C(COC(=O)[NH-])C3=CC=CC=C3C2=C1 ZZOKVYOCRSMTSS-UHFFFAOYSA-M 0.000 description 1
- NBVILZRLOFYXMF-UHFFFAOYSA-N 9h-fluorene;piperidine Chemical compound C1CCNCC1.C1=CC=C2CC3=CC=CC=C3C2=C1 NBVILZRLOFYXMF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical group CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101800000112 Acidic peptide Proteins 0.000 description 1
- 208000025978 Athletic injury Diseases 0.000 description 1
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 1
- XJKAKYXMFHUIHT-AUTRQRHGSA-N Gln-Glu-Val Chemical compound CC(C)[C@@H](C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)N)N XJKAKYXMFHUIHT-AUTRQRHGSA-N 0.000 description 1
- IRXNJYPKBVERCW-DCAQKATOSA-N Glu-Leu-Glu Chemical compound [H]N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(O)=O IRXNJYPKBVERCW-DCAQKATOSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 238000010867 Hoechst staining Methods 0.000 description 1
- ZTLGVASZOIKNIX-DCAQKATOSA-N Leu-Gln-Glu Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCC(=O)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)N ZTLGVASZOIKNIX-DCAQKATOSA-N 0.000 description 1
- AIRZWUMAHCDDHR-KKUMJFAQSA-N Lys-Leu-Leu Chemical compound [H]N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O AIRZWUMAHCDDHR-KKUMJFAQSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- SITLTJHOQZFJGG-UHFFFAOYSA-N N-L-alpha-glutamyl-L-valine Natural products CC(C)C(C(O)=O)NC(=O)C(N)CCC(O)=O SITLTJHOQZFJGG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- 108700020797 Parathyroid Hormone-Related Proteins 0.000 description 1
- 102000043299 Parathyroid hormone-related Human genes 0.000 description 1
- 241001662443 Phemeranthus parviflorus Species 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- VMLONWHIORGALA-SRVKXCTJSA-N Ser-Leu-Leu Chemical compound CC(C)C[C@@H](C([O-])=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H]([NH3+])CO VMLONWHIORGALA-SRVKXCTJSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010041738 Sports injury Diseases 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- SDSCOOZQQGUQFC-GVXVVHGQSA-N Val-His-Gln Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@@H](CCC(=O)N)C(=O)O)N SDSCOOZQQGUQFC-GVXVVHGQSA-N 0.000 description 1
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- DIPPFEXMRDPFBK-UHFFFAOYSA-N Vitamin D4 Natural products C1CCC2(C)C(C(C)CCC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C DIPPFEXMRDPFBK-UHFFFAOYSA-N 0.000 description 1
- 239000003875 Wang resin Substances 0.000 description 1
- NERFNHBZJXXFGY-UHFFFAOYSA-N [4-[(4-methylphenyl)methoxy]phenyl]methanol Chemical compound C1=CC(C)=CC=C1COC1=CC=C(CO)C=C1 NERFNHBZJXXFGY-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000001270 agonistic effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 229910052586 apatite Inorganic materials 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000013584 assay control Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000033558 biomineral tissue development Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 230000008468 bone growth Effects 0.000 description 1
- 230000010072 bone remodeling Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 210000001217 buttock Anatomy 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
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 210000003275 diaphysis Anatomy 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960002061 ergocalciferol Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000004578 fetal growth Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000001624 hip Anatomy 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 201000000916 idiopathic juvenile osteoporosis Diseases 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 108020004084 membrane receptors Proteins 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 238000010603 microCT Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000004072 osteoblast differentiation Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical compound [F-].[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 VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 description 1
- 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 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 208000001685 postmenopausal osteoporosis Diseases 0.000 description 1
- 230000009596 postnatal growth Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000033300 receptor internalization Effects 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000008458 response to injury Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960005460 teriparatide Drugs 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000012384 transportation and delivery Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 239000011653 vitamin D2 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- DIPPFEXMRDPFBK-JPWDPSJFSA-N vitamin D4 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CC[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C DIPPFEXMRDPFBK-JPWDPSJFSA-N 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
Classifications
-
- 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
- C07K14/575—Hormones
- C07K14/635—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- 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
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
-
- 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
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Endocrinology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Physical Education & Sports Medicine (AREA)
- Molecular Biology (AREA)
- Toxicology (AREA)
- Biochemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Radar Systems Or Details Thereof (AREA)
- Input Circuits Of Receivers And Coupling Of Receivers And Audio Equipment (AREA)
Description
本発明は、副甲状腺ホルモン受容体(PTHE)モジュレーター化合物ならびにそれらの作製方法および使用方法に関する。
a)Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Arg His Leu Ala Ser Met Glu Arg Val Glu Trp Leu Arg
b)Pro Val Ser Glu Ile Gln Leu Nle His Gln Arg Gly Arg His Leu Ala Ser Nle Glu Arg Val Glu Trp Leu Arg
c)Pro Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Arg His Leu Ala Ser Met Glu Arg Val Glu Trp Leu Arg
d)Ser Val Ser Glu Ile Gln Leu Nle His Asn Leu Gly Arg His Leu Ala Ser Nle Glu Arg Val Glu Trp Leu Arg
e)Ser Val Ser Glu Ile Gln Leu Nle His Gln Arg Gly Arg His Leu Ala Ser Nle Glu Arg Val Glu Trp Leu Arg
Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Arg His Leu Ala Ser Met Glu Arg Val Glu Trp Leu Arg
Ser Val Ser Glu Ile Gln Leu Nle His Asn Leu Gly Arg His Leu Ala Ser Nle Glu Arg Val Glu Trp Leu Arg
Ser Val Ser Glu Ile Gln Leu Xaa8 His Asn Leu Gly Arg His Leu Ala Ser Xaa18 Glu Arg Val Glu Trp Leu Arg
a)Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Arg His Leu Ala Ser Met Glu Arg Val Glu Trp Leu Arg Lys Leu Leu Gln Asp Val His Asn Phe(配列番号8)、
b)Pro Val Ser Glu Ile Gln Leu Nle His Gln Arg Gly Arg His Leu Ala Ser Nle Glu Arg Val Glu Trp Leu Arg Lys Leu Leu Gln Glu Val(配列番号9)、
c)Pro Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Arg His Leu Ala Ser Met Glu Arg Val Glu Trp Leu Arg Lys Leu Leu Gln Asp Val His Asn Phe(配列番号10)、
d)Ser Val Ser Glu Ile Gln Leu Nle His Asn Leu Gly Arg His Leu Ala Ser Nle Glu Arg Val Glu Trp Leu Arg Lys Leu Leu Gln Asp Val His Asn Phe(配列番号11)および
e)Ser Val Ser Glu Ile Gln Leu Nle His Gln Arg Gly Arg His Leu Ala Ser Nle Glu Arg Val Glu Trp Leu Arg Lys Leu Leu Gln Glu Val His Gln Phe(配列番号12)からなる群より選択される配列を有する中間体、またはそのC末端アミドを提供する。
骨形成は、胎児生育期および生後の成長期、ならびに成人期にも、正常な骨の再形成の一部としてゆっくりとした速度で、あるいは損傷または異常な骨量の損失に反応して急速な速度のいずれかで生じる。骨形成は、骨芽細胞の前駆細胞増殖、前駆細胞からの骨芽細胞分化、および骨芽細胞によって生成された基質の鉱化を含む多くのプロセスに関与する。用語「骨形成を誘発する」または「新骨形成を誘発する」とは、(例えば、本明細書中の実施例4Bの方法を用いて測定されるような骨ミネラル量(「BMC」)および/または骨の生体力学的強度の増加によって示されるような)骨量の純増加を意味するととられる。
本発明の化合物を、配列番号1を有する化合物の合成を例示した以下のスキームに記載したようにして調製できる。
本発明のペグ化化合物は、被験体、特にヒトへの投与に適切な薬理学的組成物に組み込まれてもよい。本発明のペグ化化合物は、単独であるいは医薬的に許容できる担体、希釈剤、および/または賦形剤と組み合わせて投与されてもよい。特に、本発明のペグ化化合物は、0.9%NaCl、3mg/mlマンニトール、pH5における20mM NaH2PO4のビヒクルで投与されてもよい。投与のための組成物は、選択された投与様式に適するように設計され、医薬的に許容できる希釈剤、担体、および/または賦形剤(例えば、分散剤、緩衝剤、界面活性剤、防腐剤、可溶化剤、等張剤、安定剤など)が、必要に応じて使用される。例えば、Remington,The Science and Practice of Pharmacy,第19版,Gennaro,Ed.,Mack Publishing Co.,Easton,PA1995(これは、一般に、実施者に公知である処方技術の概要を提供する)に記載されるように、上記組成物は従来技術に従って設計される。
本発明の別の実施形態において、上述の疾患または状態の処置または予防のための有用な物質を含む製造品が提供される。製造品は容器およびラベルを含む。適切な容器としては、例えば、ボトル、バイアル瓶、注射器、ペン、吸入器、パッチおよび試験管が挙げられる。容器は、ガラス、金属またはプラスチックのような種々の材料から形成されてもよい。容器は、疾患または状態を予防または処置するために効果的な本発明の組成物を保持し、滅菌接続部分を有してもよい(例えば、容器は、皮下注射針によって貫通可能なストッパーを有する静脈注射用溶液のバッグまたはバイアル瓶であってもよい)。容器内の活性剤は、本発明の組成物である。容器上または容器に関連したラベルは、組成物が、選択した状態を処置するのに使用されることを示す。製造品は、さらに、リン酸緩衝生理食塩水、リンガー溶液およびデキストロース溶液のような医薬的に許容できる緩衝液を含む第2の容器を含んでもよい。さらに、他の緩衝液、希釈剤、フィルター、針、注射器、および使用説明書を有する添付文書を含む、商業的および使用者の観点から望ましい他の材料を含んでもよい。
ペプチド合成を、Rapp AM RAM Fmoc−アミドポリスチレン樹脂(Rapp Polymere Tubingen、独国)(置換0.6〜0.7mmol/g)で実施する。合成は、Fmoc主鎖保護基ストラテジーを用いて実施する。さらに、芳香族、酸、塩基または高極性である任意のアミノ酸側鎖が反応しやすい。それらはまた、望まない分枝鎖が形成されるのを防ぐために保護されなければならない。この方法において、4つの主要なグループ:LysおよびTrpについてtBoc(三級ブチルオキシカルボニル);ArgについてPbf(2,2,4,6,7−ペンタメチルジヒドロベンゾフラン−5−スルホニル基);Ser、Asp、およびGluについてtBu(三級ブチル基);Gln、His、およびAsnについてTrt(トリフェニルメチル基)が存在する。アミノ酸側鎖誘導体は、Arg(Pbf)、Asn(Trt)、Asp(OtBu)、Cys(Trt)、Gln(Trt)、Glu(OtBu)、His(Trt)、Lys(Boc)、Ser(OtBu)、Trp(Boc)を使用する。結合は、ジメチルホルムアミド(DMF)中のジイソプロピルカルボジイミド(DIC)およびヒドロキシベンゾトリアゾール(HOBt)(1:1:1のモル比)で活性化した約10当量のアミノ酸を用いて実施する。1位のアミノ酸のFmoc保護基は、リジン側鎖の選択的結合を可能にするために所定の位置のままである(以下の実施例2を参照のこと)。
所定の位置でN−末端Fmoc基で結合されたペプチドを、1mLの水/アセトニトリル50/50(36.8mg、4272.9g/mol、0.0086mmol)に溶解する。1.5〜2倍のモル過剰のmPEG−2kDa NHSエステル(NOF Sunbright ME−020AS)を量りとる(39.7mg、2280平均分子量、0.017mmol)。ペプチド溶液を、2mLの40mMホウ酸ナトリウム、pH9.8緩衝液および2mLのアセトニトリルで希釈し、次いで、mPEG溶液に加える。得られた混合物をボルテックスし、次いで、室温で攪拌する。反応混合物を、分析用逆相HPLCでモニターし(実施例1に記載の方法)、通常、20〜30分の反応時間後、(約14.5分で)ペプチドピークの完全な消失および(約15.7分で)ペプチド−PEG結合体に起因するピークの出現を示す。混合物をドライアイスで冷却し、2mLのピペリジンを加えて、N−末端Fmoc基を除去する。混合物を室温で30分間攪拌し、次いで、ドライアイスで冷却し、2mLの氷酢酸で中和する(最終pH=約6−7)。ここで、分析用HPLCから、約13.2分でピペリジン−フルオレン付加物に起因するピーク、および約14.25分で脱保護されたペプチド−mPEG結合体に起因するピークが存在すべきである。混合物を水で約40mLに希釈し、A=0.05% TFA/水およびB=0.05% TFA/アセトニトリルを用いた20分にわたる0〜30%B、続いて100分にわたる30〜80%Bの2段階直線ABグラジエントにより、12mL/分で、Waters SymmetryPrep 7μm、19×300mmまたはKromasil 10μm、22×250mmのいずれかを用いて精製する。
SaOS−2骨肉腫細胞を、スティミュレーションバッファー(stimulation buffer)[1M HEPES/10% BSA/250μM IBMX(3−イソブチル−1−メチルキサンチン、MP Biomedicals)/HBSS]中に5×105細胞/mLで再懸濁する。20μL/ウェルの細胞懸濁液を、96ウェルブラックハーフエリアアッセイプレート(Costar)のウェルごとに加えて、1×104細胞/ウェルを得る。次いで、20μLの希釈した試験化合物(例えば、本発明のPTHアナログ、n=2)を、細胞にすぐに加える。試験化合物を1/2log希釈として調製し、3μM〜0.1nMの滴定範囲にわたってアッセイする。プレートを室温で1時間インキュベートする。別の96ウェルアッセイプレートもまた、標準曲線としてcAMPを含むように調製する。cAMP標準を、400〜0.0012pmoles/ウェル(40μL/ウェル)(n=6)の滴定範囲にわたってスティミュレーションバッファー(stimulation buffer)中で1/2log希釈として調製する。1時間のインキュベーション工程後、製造業者の指示書に従って、cAMPを、HTRF(登録商標)(homogeneous time resolved fluorescence)cAMPダイナミック2キット(Cisbio)を用いてアッセイする。
A.若い成体の骨量減少性の卵巣切除したラット
約3ヶ月齢の雌のSprague−Dawleyラットを、偽コントロールを除いて卵巣切除して、自由に食物(0.5%Caおよび0.4%Pを含むTD89222、Teklad、マディソン、WI)および水に接近できる状態で22℃にて12時間明暗サイクルを維持する。卵巣切除した(Ovx)ラットを、25日間、骨を損失させ、次いで、重さを量り、処置群に無作為に分ける。処置は、1ヶ月間、0.9%NaCl、3mg/mlマンニトール、pH5における20mM NaH2PO4のビヒクル中の(以下の表2に示すように)種々の用量で、本発明の化合物のを皮下注射して行う。ラットに、3日または4日ごと(ヒトでおおよそ1週間に1度の投与に相当)、化合物を注射する。偽およびOvxコントロールを、ビヒクルのみで処置する(「偽ビヒクルコントロール」および「ovxビヒクルコントロール」)。血清を、解剖時(最後の注射後約24時間目)に、イソフルラン麻酔の下で最後の注射後約24時間目に心穿刺によって収集し、臨床化学分析装置(日立917、東京、日本)を用いて解析する。
+アッセイパラメータ内で高カルシウム血症が、試験化合物の投与後、24時間目に観察される用量(回帰直線に適合させて、補間によって測定した場合)
**「>」は、記載した用量が、試験した最も高い用量であり、本明細書で定義した場合の高カルシウム血症には、その用量では到達しなかったことを示す。
この実施齢において、偽ビヒクルコントロールレベルに対するOvxラットの骨の生体力学的強度、BMDおよびBMCを増加させる本発明のペグ化化合物の能力を測定する。骨の生体力学的強度に対する化合物の効果は、BMDより臨床効果の面でより優れた予測因子であると期待される。脊椎のBMDは、脊椎骨折の発生率を減少させるための骨粗鬆症治療の臨床効果をわずかに予測する(Cummingsら,Am.Journal of Medicine,112:281−289,2002;Sarkarら,J.Bone&Mineral Research 17:1−20,2002)。PTH(1−34)は、脊椎骨折および非脊椎骨折の両方の危険性を減少させるため(Neerら,NEJM,344:1434−1441,2001)、腰椎および2箇所の非脊椎部位、すなわち、大腿骨骨幹中部および大腿骨頸部において骨の生体力学的強度を増加させるかどうかを実証するために、本発明の化合物の効果を解析する。
++偽レベルの脊椎骨ミネラル濃度(BMD)が、このアッセイパラメータ内で達成される用量
*偽レベルの脊椎骨ミネラル量(BMC)が、このアッセイパラメータ内で達成される用量
**偽およびポジティブコントロール(3−5μg/kg/d PTH(1−38))に匹敵する脊椎強度が、達成される用量(アッセイコントロール内で)
^偽ビヒクルコントロールおよび3−5μg/kg/d PTH(1−38)のポジティブコントロールに匹敵する骨幹中部強度が、達成される用量
^^偽ビヒクルコントロールおよび3−5μg/kg/d PTH(1−34)のポジティブコントロールに匹敵する大腿骨頸部強度が、達成される用量。
結合mPEGが2kD mPEGである、配列番号1を有する本発明の化合物を、結合mPEGが5kD mPEGである、配列番号1を有する本発明の化合物と直接比較する。高齢の骨量減少を示す卵巣切除したラットに、8週間、ビヒクル単独、または2kDペグ化配列番号1の化合物、または5kDペグ化配列番号1の化合物を6日ごとに投与する(表5および6に示されるようにnmol/kg)前に、1ヶ月間、骨を損失させる。表5は、投与後24時間の平均血清カルシウム(mg/dL)値を示す。表6は平均BMD(mg/cc)を示す。
6ヶ月齢の卵巣切除したSprague−Dawleyラットを、自由に食物(0.5%Caおよび0.4%Pを含むTD89222、Teklad、マディソン、WI)および水に接近できる状態で22℃にて12時間明暗サイクルを維持する。卵巣切除したラットを、3ヶ月間、rhPTH(1−34)で処置する前に、1ヶ月間、骨を損失させる。高齢の骨量減少を示す卵巣切除したそのラットに、12週間、0、10または30μg/kgのヒトPTH(1−34)を週に1回、皮下注射する。偽およびovxコントロールにビヒクルのみを注射する。解剖時に腰椎を切除し、マイクロ−CT(Stratec)によって解析し、次いで、生体力学的試験の準備をする。ニュートン(N)での強度を、機能停止まで脊椎骨標本を負荷することによって評価する。ovxビヒクルコントロールに対する有意性が、以下の表7の*によって示される(Fishers PLSD、P<0.05)。モデルデータを以下の表7に提供する。
本発明の化合物についてのPTHR1(PTH受容体1)の内在化の動力学を、膜受容体へのリガンド結合により測定する。HEK293細胞に、PTHR−emGFPプラスミド(Invitrogen)をトランスフェクトする。
Claims (9)
- mPEGが、2000〜5000ダルトンの平均分子量を有する、請求項1〜4のいずれか1項に記載の化合物、またはその医薬的に許容できる塩。
- mPEGが、2000ダルトンの平均分子量を有する、請求項1〜4のいずれか1項に記載の化合物、またはその医薬的に許容できる塩。
- 新生骨形成ならびに骨量および骨の生体力学的強度の増加が哺乳動物において有益であり、骨粗鬆症、骨減少症、骨折、脊椎固定術、骨インプラント、関節インプラント、歯科インプラント、および歯周病を含む状態を処置するための医薬を製造するための請求項1〜4のいずれか1項に記載の化合物、またはその医薬的に許容できる塩の使用。
- mPEGが2000〜5000ダルトンの平均分子量を有する、請求項7に記載の使用。
- 該哺乳動物がヒトである、請求項7に記載の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US82938306P | 2006-10-13 | 2006-10-13 | |
US60/829,383 | 2006-10-13 | ||
PCT/US2007/080367 WO2008048784A1 (en) | 2006-10-13 | 2007-10-04 | Pegylated pth as pth receptor modulators and uses thereof |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2010506844A JP2010506844A (ja) | 2010-03-04 |
JP2010506844A5 JP2010506844A5 (ja) | 2010-10-07 |
JP5200027B2 true JP5200027B2 (ja) | 2013-05-15 |
Family
ID=42828673
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009532504A Expired - Fee Related JP5200027B2 (ja) | 2006-10-13 | 2007-10-04 | Pth受容体モジュレーターとしてのペグ化pthおよびその使用 |
Country Status (16)
Country | Link |
---|---|
US (1) | US7820179B2 (ja) |
EP (1) | EP2084183B1 (ja) |
JP (1) | JP5200027B2 (ja) |
KR (1) | KR101108354B1 (ja) |
CN (1) | CN101522709B (ja) |
AT (1) | ATE469173T1 (ja) |
AU (1) | AU2007313001B2 (ja) |
BR (1) | BRPI0719885B8 (ja) |
CA (1) | CA2672907C (ja) |
DK (1) | DK2084183T3 (ja) |
EA (1) | EA014696B1 (ja) |
MX (1) | MX2009003740A (ja) |
NO (1) | NO341986B1 (ja) |
PL (1) | PL2084183T3 (ja) |
SI (1) | SI2084183T1 (ja) |
WO (1) | WO2008048784A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MY196308A (en) * | 2016-03-01 | 2023-03-24 | Ascendis Pharma Bone Diseases As | PTH Prodrugs |
HRP20231079T1 (hr) | 2016-09-29 | 2023-12-22 | Ascendis Pharma Bone Diseases A/S | Režim za doziranje pth spoja s kontroliranim oslobađanjem |
DK3518961T3 (da) | 2016-09-29 | 2023-04-24 | Ascendis Pharma Bone Diseases As | PTH-forbindelser med lave forhold mellem top og bund |
US20210214408A1 (en) * | 2018-05-30 | 2021-07-15 | Purdue Research Foundation | Targeting anabolic drugs for accelerated fracture repair |
Family Cites Families (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4179337A (en) * | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
FR2550204B1 (fr) * | 1983-08-05 | 1987-11-13 | Toyo Jozo Kk | Derives peptidiques de (nle8,nle1b, tyr34)-h-pth |
JPS6360940A (ja) | 1986-09-01 | 1988-03-17 | Toyo Jozo Co Ltd | 白内障の予防または治療剤 |
US4771124A (en) * | 1987-05-26 | 1988-09-13 | Merck & Co., Inc. | Parathyroid hormone antagonists with simplified synthetic methodology |
EP0293158A3 (en) | 1987-05-26 | 1990-05-09 | Merck & Co. Inc. | Parathyroid hormone antagonists |
JPH0532696A (ja) | 1990-09-28 | 1993-02-09 | Takeda Chem Ind Ltd | 副甲状腺ホルモン誘導体 |
JPH05271279A (ja) * | 1991-08-07 | 1993-10-19 | Takeda Chem Ind Ltd | ヒト副甲状腺ホルモンムテインおよびその製造法 |
US5814603A (en) | 1992-06-12 | 1998-09-29 | Affymax Technologies N.V. | Compounds with PTH activity |
US5589452A (en) * | 1992-07-14 | 1996-12-31 | Syntex (U.S.A.) Inc. | Analogs of parathyroid hormone and parathyroid hormone related peptide: synthesis and use for the treatment of osteoporosis |
AU672790B2 (en) | 1992-07-15 | 1996-10-17 | Novartis Ag | Variants of parathyroid hormone and its fragments |
US6110892A (en) * | 1994-06-20 | 2000-08-29 | National Research Council Of Canada | Parathyroid hormone analogues for the treatment of osteoporosis |
CA2126299C (en) * | 1994-06-20 | 2000-12-12 | Gordon E. Willick | Parathyroid hormone analogues for the treatment of osteoporosis |
US5747456A (en) | 1994-12-19 | 1998-05-05 | Beth Israel Deaconess Medical Center | Continuous low-dose administration of parathyroid hormone or its agonist |
US5717062A (en) | 1995-06-07 | 1998-02-10 | Beth Israel Hospital Association | Cyclic analogs of PTH and PTHrP |
CA2178894A1 (en) | 1995-06-15 | 1996-12-16 | Tsunehiko Fukuda | Parathyroid hormone derivatives and their use |
US5955574A (en) | 1995-07-13 | 1999-09-21 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A. | Analogs of parathyroid hormone |
US6544949B1 (en) * | 1995-07-13 | 2003-04-08 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Analogs of parathyroid hormone |
US5723577A (en) | 1995-07-13 | 1998-03-03 | Biomeasure Inc. | Analogs of parathyroid hormone |
BR9711002B1 (pt) | 1996-08-02 | 2011-09-06 | análogo do hormÈnio da paratireóide para o tratamento de osteoporose. | |
KR100351213B1 (ko) * | 1997-05-14 | 2002-09-05 | 아벤티스 파마슈티칼스 인크. | 펩타이드 부갑상선 호르몬 유사체 및 이를 포함하는 약제학적 조성물 |
EP1030658A1 (en) * | 1997-10-14 | 2000-08-30 | Eli Lilly And Company | Method of building and maintaining bone |
IL138214A0 (en) | 1998-03-09 | 2001-10-31 | Zealand Pharmaceuticals As | Pharmacolgically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis |
CA2325572A1 (en) * | 1998-04-15 | 1999-10-21 | Aventis Pharmaceuticals Products Inc. | Process for the preparation of resin-bound cyclic peptides |
ES2302374T3 (es) | 1998-05-05 | 2008-07-01 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Compuesto selectivo de receptores pth2. |
US6316410B1 (en) * | 1999-09-22 | 2001-11-13 | National Research Council Of Canada | Parathyroid hormone analogues for the treatment of osteoporosis |
AU7734800A (en) | 1999-09-29 | 2001-04-30 | General Hospital Corporation, The | Polypeptide derivatives of parathyroid hormone (pth) |
US7022815B1 (en) * | 1999-09-29 | 2006-04-04 | The General Hospital Corporation | Polypeptide derivatives of parathyroid hormone (PTH) |
US20050124537A1 (en) * | 2000-04-27 | 2005-06-09 | Amgen Inc. | Modulators of receptors for parathyroid hormone and parathyroid hormone-related protein |
US6756480B2 (en) | 2000-04-27 | 2004-06-29 | Amgen Inc. | Modulators of receptors for parathyroid hormone and parathyroid hormone-related protein |
JP4837888B2 (ja) * | 2001-07-23 | 2011-12-14 | ザ ジェネラル ホスピタル コーポレイション | コンホメーションが拘束された副甲状腺ホルモン(pth)類似体 |
JPWO2003064462A1 (ja) * | 2002-02-01 | 2005-05-26 | 中外製薬株式会社 | Peg結合pth又はpeg結合pth誘導体 |
AU2003251527A1 (en) * | 2002-06-13 | 2003-12-31 | Beth Israel Deaconess Medical Center, Inc. | Analogs of parathyroid hormone and pth-related protein as bone anabolic agents |
TW533925U (en) * | 2002-09-26 | 2003-05-21 | Lee Yeong Ind Co Ltd | Improvement of speed-changing transmission mechanism for cutting tools of drill sharpening machine |
EP1567178A4 (en) | 2002-11-01 | 2009-07-15 | Amgen Inc | MODULATORS OF RECEPTORS FOR NEUTRAL THERAPY HORMONE AND SIDE-HORSE HORMONE-RELATED PROTEINS |
KR101025143B1 (ko) | 2002-12-31 | 2011-04-01 | 넥타르 테라퓨틱스 | 가수분해상으로 안정한 말레이미드-종결 중합체 |
EP1607095A1 (en) * | 2003-03-25 | 2005-12-21 | Sekisui Chemical Co., Ltd. | Antipruritic composition for external use on skin |
US20040220094A1 (en) * | 2003-05-01 | 2004-11-04 | Skinner Keith K. | Inverse agonist and agonist peptides that stimulate/inhibit hair growth |
EP1758927A4 (en) | 2004-01-21 | 2008-09-17 | Unigene Lab Inc | PARATHYROID HORMONE AMIDE FRAGMENTS AND USES THEREOF |
-
2007
- 2007-10-04 JP JP2009532504A patent/JP5200027B2/ja not_active Expired - Fee Related
- 2007-10-04 BR BRPI0719885A patent/BRPI0719885B8/pt not_active IP Right Cessation
- 2007-10-04 WO PCT/US2007/080367 patent/WO2008048784A1/en active Application Filing
- 2007-10-04 KR KR1020097007424A patent/KR101108354B1/ko active IP Right Grant
- 2007-10-04 AU AU2007313001A patent/AU2007313001B2/en not_active Ceased
- 2007-10-04 EA EA200970376A patent/EA014696B1/ru not_active IP Right Cessation
- 2007-10-04 US US12/440,619 patent/US7820179B2/en not_active Expired - Fee Related
- 2007-10-04 PL PL07843791T patent/PL2084183T3/pl unknown
- 2007-10-04 SI SI200730296T patent/SI2084183T1/sl unknown
- 2007-10-04 EP EP07843791A patent/EP2084183B1/en active Active
- 2007-10-04 CA CA2672907A patent/CA2672907C/en not_active Expired - Fee Related
- 2007-10-04 AT AT07843791T patent/ATE469173T1/de active
- 2007-10-04 CN CN2007800382095A patent/CN101522709B/zh not_active Expired - Fee Related
- 2007-10-04 DK DK07843791.0T patent/DK2084183T3/da active
- 2007-10-04 MX MX2009003740A patent/MX2009003740A/es active IP Right Grant
-
2009
- 2009-04-28 NO NO20091691A patent/NO341986B1/no not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
CA2672907A1 (en) | 2008-04-24 |
KR20090067168A (ko) | 2009-06-24 |
AU2007313001B2 (en) | 2012-03-22 |
EA014696B1 (ru) | 2010-12-30 |
KR101108354B1 (ko) | 2012-01-25 |
WO2008048784A1 (en) | 2008-04-24 |
EA200970376A1 (ru) | 2009-10-30 |
US7820179B2 (en) | 2010-10-26 |
EP2084183B1 (en) | 2010-05-26 |
BRPI0719885A2 (pt) | 2014-04-29 |
CN101522709A (zh) | 2009-09-02 |
US20090253630A1 (en) | 2009-10-08 |
MX2009003740A (es) | 2009-04-22 |
ATE469173T1 (de) | 2010-06-15 |
CA2672907C (en) | 2013-08-06 |
NO20091691L (no) | 2009-05-11 |
EP2084183A1 (en) | 2009-08-05 |
CN101522709B (zh) | 2013-03-20 |
AU2007313001A1 (en) | 2008-04-24 |
JP2010506844A (ja) | 2010-03-04 |
SI2084183T1 (sl) | 2010-09-30 |
NO341986B1 (no) | 2018-03-12 |
DK2084183T3 (da) | 2010-08-16 |
BRPI0719885B1 (pt) | 2018-12-11 |
PL2084183T3 (pl) | 2010-10-29 |
BRPI0719885B8 (pt) | 2021-05-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2007056362A2 (en) | Glucagon analogs exhibiting physiological solubility and stability | |
WO2021068550A1 (en) | Active polypeptide compound | |
JP5200027B2 (ja) | Pth受容体モジュレーターとしてのペグ化pthおよびその使用 | |
CN109153712B (zh) | Peg化生物活性肽及其用途 | |
US10947285B2 (en) | Compounds, compositions and uses thereof for improvement of bone disorders | |
ES2343917T3 (es) | Pth pegilados como moduladores del receptor pth y uso de los mismos. | |
JP5529014B2 (ja) | 部位特異的なペグ化をされた直鎖状のサケカルシトニン類似体 | |
CN116801900A (zh) | 用于治疗骨折的化合物、组合物和使用方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100823 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20100823 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120918 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20121213 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20130115 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130208 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20160215 Year of fee payment: 3 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 Ref document number: 5200027 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |