JPH08503692A - Parathyroid hormone fragments and analogs - Google Patents
Parathyroid hormone fragments and analogsInfo
- Publication number
- JPH08503692A JPH08503692A JP6505568A JP50556894A JPH08503692A JP H08503692 A JPH08503692 A JP H08503692A JP 6505568 A JP6505568 A JP 6505568A JP 50556894 A JP50556894 A JP 50556894A JP H08503692 A JPH08503692 A JP H08503692A
- Authority
- JP
- Japan
- Prior art keywords
- pth
- parathyroid hormone
- patient
- human parathyroid
- hormone fragment
- 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.)
- Pending
Links
- 239000012634 fragment Substances 0.000 title claims abstract description 23
- 108090000445 Parathyroid hormone Proteins 0.000 title claims description 207
- 102000003982 Parathyroid hormone Human genes 0.000 title description 145
- 239000000199 parathyroid hormone Substances 0.000 title description 143
- 229960001319 parathyroid hormone Drugs 0.000 title description 143
- 238000011282 treatment Methods 0.000 claims abstract description 21
- 101001135770 Homo sapiens Parathyroid hormone Proteins 0.000 claims abstract description 18
- 101001135995 Homo sapiens Probable peptidyl-tRNA hydrolase Proteins 0.000 claims abstract description 18
- 102000058004 human PTH Human genes 0.000 claims abstract description 18
- 210000000988 bone and bone Anatomy 0.000 claims abstract description 14
- 150000001413 amino acids Chemical class 0.000 claims abstract description 8
- 150000002148 esters Chemical class 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 claims abstract description 5
- 125000001433 C-terminal amino-acid group Chemical group 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 21
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- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 208000037147 Hypercalcaemia Diseases 0.000 claims description 3
- 201000002980 Hyperparathyroidism Diseases 0.000 claims description 3
- 210000004027 cell Anatomy 0.000 claims description 3
- 230000000148 hypercalcaemia Effects 0.000 claims description 3
- 208000030915 hypercalcemia disease Diseases 0.000 claims description 3
- OCLLVJCYGMCLJG-CYBMUJFWSA-N (2r)-2-azaniumyl-2-naphthalen-1-ylpropanoate Chemical compound C1=CC=C2C([C@@](N)(C(O)=O)C)=CC=CC2=C1 OCLLVJCYGMCLJG-CYBMUJFWSA-N 0.000 claims description 2
- BKQQPCDQZZTLSE-UHFFFAOYSA-N 2-amino-3-naphthalen-1-ylpropanoic acid;hydrochloride Chemical compound Cl.C1=CC=C2C(CC(N)C(O)=O)=CC=CC2=C1 BKQQPCDQZZTLSE-UHFFFAOYSA-N 0.000 claims description 2
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- 108090000765 processed proteins & peptides Proteins 0.000 description 18
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- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
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- GZCWLCBFPRFLKL-UHFFFAOYSA-N 1-prop-2-ynoxypropan-2-ol Chemical compound CC(O)COCC#C GZCWLCBFPRFLKL-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 102000013563 Acid Phosphatase Human genes 0.000 description 1
- 108010051457 Acid Phosphatase Proteins 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
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- 102000004067 Osteocalcin Human genes 0.000 description 1
- 108090000573 Osteocalcin Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102000007591 Tartrate-Resistant Acid Phosphatase Human genes 0.000 description 1
- 108010032050 Tartrate-Resistant Acid Phosphatase Proteins 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 229930003316 Vitamin D Natural products 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
- GELXFVQAWNTGPQ-UHFFFAOYSA-N [N].C1=CNC=N1 Chemical compound [N].C1=CNC=N1 GELXFVQAWNTGPQ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
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- 238000004458 analytical method Methods 0.000 description 1
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- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000007900 aqueous suspension 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
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000010072 bone remodeling Effects 0.000 description 1
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- 229920006026 co-polymeric resin Polymers 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- GCFAUZGWPDYAJN-UHFFFAOYSA-N cyclohexyl 3-phenylprop-2-enoate Chemical compound C=1C=CC=CC=1C=CC(=O)OC1CCCCC1 GCFAUZGWPDYAJN-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
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- 239000007920 enema Substances 0.000 description 1
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- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000003054 hormonal effect Effects 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
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- 239000000203 mixture Substances 0.000 description 1
- 238000007491 morphometric analysis Methods 0.000 description 1
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- 238000013425 morphometry Methods 0.000 description 1
- 210000002184 nasal cartilage Anatomy 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 230000001582 osteoblastic effect Effects 0.000 description 1
- 230000000849 parathyroid Effects 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
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- 239000000902 placebo Substances 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 208000011865 skeletal system disease Diseases 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
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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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Endocrinology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
(57)【要約】 本発明は、そのC-末端アミノ酸がアミノ酸35〜38であり、そして少なくとも第一N-末端アミノ酸が除去されているヒト上皮小体ホルモン断片、又はそのアナログ又は誘導体あるいはその医薬として許容される塩又は加水分解性エステル並びに骨変性疾患の治療におけるその使用に関する。 (57) [Summary] The present invention relates to a human parathyroid hormone fragment whose C-terminal amino acid is amino acids 35 to 38 and at least the first N-terminal amino acid is removed, or an analog or derivative thereof or a pharmaceutically acceptable salt thereof. Or a hydrolysable ester and its use in the treatment of bone degenerative diseases.
Description
【発明の詳細な説明】 上皮小体ホルモン断片及びアナログ 本発明は、上皮小体ホロモン・ペブチド(parathyroid hormone peptide)及 び骨疾患の治療におけるそれらの使用に関する。特に、本発明は、公知の上皮小 体ホルモン・ペプチドに関連した不所望の副作用を伴わずに骨形成を刺激するヒ ト上皮小体ホルモン・ペプチド断片及びアナログに関する。 変性骨疾患、例えば、骨粗しょう症は、最も頻繁に発生する骨格系疾患である 。それは、骨質量の減少をもたらす骨形成と骨再吸収との間の細胞生物学的活性 の不均衡を特徴とする。骨粗しょう症及び減少骨質量の症状の治療に関連する問 題は広く未解決である。これは、骨粗しょう症の後期段階において見られるよう に、骨質量のかなりの減少が生じ、そして骨の再モデリングが減少するケースに おいては、特に真実である。首尾よい治療は、その疾患の進行を防止するのみな らず、新たな骨形成をも剌激しなければならない。骨粗しょう症の現在の治療は 、ホルモン療法、カルシウム及びビタミンD補強及びフッ化ナトリウム処理を含 むが、そのほとんどが満足できるものではない。骨損失は、このような治療によ り遅延化されることができるが、骨質量における全正味増加量は限定されている 。 上皮小体ホルモン(PTH)がカルシウム及び燐代謝を調節し、そして骨代謝に 対する有効な効果をもつということが時々知られてきた。しかしなから、PTHの 投与は、骨破壊に関連する破骨細胞の速い増殖、並びに骨形成に必要な骨芽細胞 の遅い剌激を、誘導する。PTHを作り上げる84アミノ酸の最初の34 N-末端アミノ 酸、(1-34)PTHは、その生来のホルモンの生物学的活性のほとんど全てに責任 を負 っている。多数の臨床試験及び実験的研究は、PTHと(1-34)PTHの両方が骨粗し ょう症の治療において非常に限定された臨床的価値のみを有することを示してい る。なぜなら、破骨細胞活性及び骨芽細胞活性をそれらが剌激することにより、 骨質量における僅かで矛盾し且つ予測不能の全正味増加量があるためである。さ らに、PTH又は(1-34)PTHの連続使用は、治療開始後12〜18カ月以内にタキフィ ラキシー(tachiphylaxis)を誘導する。最初の1又は2のアミノ酸の除去は、 インビトロにおける破骨細胞の刺激及び骨再吸収に関連したPTH及び(1-34)PTH の活性を減少させることが知られている。上皮小体ホルモン断片(3-34)PTHが 、同時発生の骨再吸収を伴わずに骨芽細胞増殖及び骨形成を刺激するであろうと いうことが示唆されている。しかしながら、(3-34)PTHは、不所望の抗体形成 及び治療に対する抵抗性を引き起こす(1-34)PTHに類似した抗原活性及びタキ フィラシーをもつ。現在知られているPTH断片及びアナログの全ては、それらの 骨再吸収活性、抗原性又はタキフィラシーのために、骨粗しょう症の治療におい て限定された価値を有する。 C-末端アミノ酸がアミノ酸35〜38、好ましくは37又は38であり、そして少なく とも第一N-末端アミノ酸が除去されているヒト上皮小体ホルモン断片、並びにそ のアナログ及び誘導体が、不所望のレべルの骨再吸収、抗体形成、又はアナフィ ラキシーを伴わずに、骨芽細胞活性を刺激し、そして骨形成を最大化するという ことが、今般発見された。本発明に係るヒト上皮小体ホルモン断片は、式(m-n )PTHによる標準的な命名法に従って表されることかでき、式中、mが第一N-末 端アミノ酸の番号であり、そして本発明においては少なくとも2であり、そして nがアミノ酸35〜38である。好ましいPTH断片、アナログ、及び誘導体において は、mが2〜28であり、そして: a)(3-38)PTH、(4-38)PTH、(5-38)PTH、(6-38)PTH、(7-38)PTH、 (8-38)PTH、(9-38)PTH、(10-38)PTH、(11-38)PTH、(12-38)PTH、(13 -38)PTH、(14-38)PTH、(15-38)PTH、(16-38)PTH、(17-38)PTH、(18-3 8)PTH、(19-38)PTH、(20-38)PTH、(21-38)PTH、(22-38)PTH、(23-38 )PTH、(24-38)PTH、(25-38)PTH、(26-38)PTH、(27-38)PTH又は(28-38 )PTH、特に(3-38)PTH; b)(3-37)PTH、(4-37)PTH、(5-37)PTH、(6-37)PTH、(7-37)PTH、 (8-37)PTH、(9-37)PTH、(10-37)PTH、(11-37)PTH、(12-37)PTH、(13 -37)PTH、(14-37)PTH、(15-37)PTH、(16-37)PTH、(17-37)PTH、(18-3 7)PTH、(19-37)PTH、(20-37)PTH、(21-37)PTH、(22-37)PTH、(23-37 )PTH、(24-37)PTH、(25-37)PTH、(26-37)PTH、(27-37)PTH又は(28-37 )PTH、特に(3-37)PTH; c)(2-35)PTH、(2-36)PTH、(2-37)PTH又は(2-38)PTH、特に(2-37) PTH及び(2-38)PTH; d)a)、b)又はc)の、[Tyr34]、[Nle8.18Tyr34]、[Phe23]、[Le u23]、[Nle23]、[Val23]、[Tyr23]、[アルファ-ナフチルアラニン23] 、又は[ベータ-ナフチルアラニン23]アナログ;又は e)a)、b)、c)又はd)のC-末端アミド誘導体、 {式中、PTHがヒト上皮小体ホルモン(hPTH)である。}、又は医薬として許 容される塩又はその加水分解性エステルを含んで成る。 本発明に係る化合物は、公知の技術、例えば、Merrifieldにより開発された固 相ペプチド合成法("Solid Phase Peptide Synthesis",Advances in Enzymolog y,32:221-296,1969)により合成される。ペプチドのC-末端アミノ酸をカルボ キシル基を介して固体支持体に共有結合させる。所望のペプチド配列を、保護形 態における単一アミノ酸を、そのアミノ末端に向かってそのカルボキシルから成 長す るペプチド鎖に段階的にカップリングさせることにより、製造する。それぞれの アミノ酸がほとんど同じシリーズの反応により結合されるので、この合成におけ るやっかいな戦略の必要性は最小化される。この方法は速く;そして所望のペプ チド鎖の製造後、そのペプチドを適宜標準的な技術により容易に脱保護すること ができる。 あるいは、ペプチド断片を組換えDNA技術を使用して調製することができる。 所望のペプチドのためのDNAを商業的に入手可能なオリゴヌクレオチド合成装置 (gene machine)、例えば、Applied Biosystem Inc.自動合成装置により、その 製造者の手順を使用して、合成することができる。次に、そのDNAを慣用の宿主 、例えは、大腸菌(E.coli)、酵母又は哺乳類細胞内で好適なベクターを使用し て発現させ、所望のペプチド断片を産生させる。 先の上皮小体ホルモン・ペプチドは、1日当たり100μg/kg体重と1000μg/kg 体重との間のペプチドの投与量を与えられた50グラムを超える体重の雄又は雌の ラットにおいて示されたように、骨形成の刺激において有用である。この動物を それぞれ12動物の5群に分け、1カ月までの間毎日皮下注射を与えた。群1は、 偽薬対照であり;群2は、100μg/kg/日の標準(1-38)hPTHを受容し;群3は、 100μg/kg/日のペプチドを受容し;群4は、400μg/kg/日のペプチドを受容し; そして群5は、1000μg/kg/日のペプチドを受容する。それぞれの群の動物のた めに、骨代謝における変化を反映する血清タンパク質及び酵素のレベルを治療の 終りに検定する(例えば、血清オステオカルシン(osteocalcin)、血清アルカ リ性ホスファターゼ、及び血清酒石酸耐性酸ホスファターゼ)。すべての動物が 治療:(1)骨中への放射能の取り込みを測定するための25μCi/100g体重にお ける[3H]-テトラサイクリン;又は(2)形態計測による鉱物並置速度/骨形 成速度の測定のために新たに鉱物化した海 綿骨を蛍光標識するためのテトラサイクリン化合物の2の注射-殺しの前4〜5 日間の第一注射及び殺しの前1〜2日間の第二注射、のいずれか、の最後の週の 間にテトオラサイクリン化合物を受容する。動物を治療の終わりに殺し、そして 大腿、脊椎、及び脛骨を、海綿及び/又は皮質骨のラジオアイソトープ分析又は 形態計測分析のいずれかのために、そして骨抽出物(例えば、アルカリ性ホスフ ァターゼ及び酒石酸耐性酸ホスファターゼ)の分析のために採取した。 本発明に係るPTHホルモン断片、アナログ、及び誘導体は、それ故、変性骨疾 患の治療において有用であり、そして骨粗しょう症又は高カルシウム血症の治療 方法であって本発明に係る上皮小体ホルモン・ペプチドの治療的有効投与量をそ の治療の必要な患者に投与することを介するものを提供する。さらに、本発明は 、上皮小体亢進症(hyperparathyroidism)、特に高カルシウム血発症、腎不全 、又は高血圧として現れる上皮小体亢進症の治療方法であって、その治療の必要 な被験者に本発明に係る上皮小体ホルモンの治療的に有効な量を投与することを 含んで成る方法を提供する。本発明は、さらに、ペプチド・ホルモン様分子を過 剰生産する腫瘍又は他の異常細胞により作り出される病的状態を治療する方法並 びに炎症、アレルギー性応答又は超活性リンパ球を含んで成る免疫疾患の治療方 法であって、その治療に必要な被験者に本発明に係るペプチド・ホルモン断片、 アナログ、又は誘導体の治療的有効量を投与することを含んで成る方法を、提供 する。 上記用途のために投与される本発明に係る上皮小体ホルモン・ペプチドの量は 、使用されるペプチド及び治療を経験する被験者に依存して変化するであろう。 しかしながら、満足できる結果が、ペブチドが毎日又は断続的に、そして所望に より、4-週又は6-週サイク ル、その五の1〜4週間のペプチド不含期間、投与されるときに、得られる。本 発明に係るペプチドは、特に骨粗しょう症被験者又は減少した骨質量をもつ被験 者、例えば、ヒトに、20-2000μg/日、好ましくは100-1000μg/日の投与量レン ジにおいて、投与されることができる。それは、24時間にわたる単一投与又は幾 つかの投与において又は連続静脈内注入として投与されることができる。治療の 間又は後に、上皮小体ペプチドにより影響されることができるカルシウム代謝の すべてのパラメーターが測定されなければならない。従って、骨、腸、及び腎臓 カルシウム代謝並びに1,25-(OH)2-ビタミンD合成がその治療の効果及び可 能性のある代謝副作用を測定するためにモニターされなけらばばらない。 本発明に係るペプチドは、経腸的、非経口的、又は皮下的に、慣用の医薬担体 と混合されて投与される。それらは、錠剤又はカプセルの形態で経口的に又は溶 液、例えば、滅菌注射可能溶液、懸濁液、例えば、水性懸濁液、として非経口的 に、又は活性成分が公知技術によりコートされ、崩壊及び吸収を遅らせ、そして それにより非常に長い時間にわたり持続作用を提供するような貯蔵形態で、投与 されることができる。それらは、また、スプレーの形態で鼻から又は座剤又は浣 腸剤の形態で直腸から投与されることができる。それらは、好ましくは、皮下的 に又は直腸から、そして特に鼻から投与される。なぜなら、それらは、骨再吸収 を剌激せず、そして鼻の軟骨の腐食を引き起こさないからである。mが18〜28で あるより小さなPTH断片が鼻からの投与に特に有用である。なぜなら、それらは 、鼻の膜を通して容易に吸収されるからである。本発明に係る医薬組成物は本分 野において開示されているように配合され、そして担体又はアジュバントとの組 み合わせにおいて約90%までの活性成分を含むことができる。 実施例1 (3-38)PTHの合成 上皮小体ホルモン断片(3-38)PTHの合成をペプチド合成装置を使用するMerri fieldの固相法により行う。第三ブチルオキシカルボニル(Boc)基をカップリン グの間にそれぞれのアミノ酸のアルファ-アミノ基を保護するために使用する。 他の官能側基を以下のように保護する:(a)セリンのヒドロキシル基をその0 −ベンジル・エーテルとして保護し;(b)チロシンのヒドロキシル基をその0- 2,6-ジクロロベンジル・エーテル又はp-ブロモベンジルオキシカルボニル・エス テルとして保護し;(c)グルタミン酸及びアスパラギン酸のカルボキシル基を そのベンジル又はシクロヘキシル・エステルとして保護し;(d)ヒスチジンの イミダゾール窒素をベジルオキシメチル(BOM)基により保護し;(e)アルギ ニンのグアニジン官能基をそのp-トルエンスルホニル基により保護し;そして( f)トリプトファンのインドール・イミンをそのホルミル基により保護する。ペ プチド-樹脂合成をその合成装置の製造者特定プロトコールを使用して行う。合 成が完了した後、そのペプチドを脱保護し、そのコポリマー樹脂から解裂させ、 そして製造者のプロトコールに従って精製し、(3-38)PTHを得る。 上記の手順に従って、(2-35)PTH、(2-36)PTH、(2-37)PTH、(2-38)PTH 、(4-38)PTH、(5-38)PTH、(6-38)PTH、(7-38)PTH、(8-38)PTH、(9-3 8)PTH、(10-38)PTH、(11-38)PTH、(12-38)PTH、(13-38)PTH、(14-38 )PTH、(15-38)PTH、(16-38)PTH、(17-38)PTH、(18-38)PTH、(19-38) PTH、(20-38)PTH、(21-38)PTH、(22-38)PTH、(23-38)PTH、(24-38)PT H、(25-38)PTH、(26-38)PTH、(27-38)PTH、(28-38)PTH、(3-37)PTH、 (4-37)PTH、(5-37)PTH、(6-37)PTH、(7-37)PTH、(8-37)PTH、(9-37 )PTH、(10-37)PTH、(11-37)PTH、(1 2-37)PTH、(13-37)PTH、(14-37)PTH、(15-37)PTH、(16-37)PTH、(17- 37)PTH、(18-37)PTH、(19-37)PTH、(20-37)PTH、(21-37)PTH、(22-37 )PTH、(23-37)PTH、(24-37)PTH、(25-37)PTH、(26-37)PTH、(27-37) PTH、又は(28-37)PTHを同様に合成する。DETAILED DESCRIPTION OF THE INVENTION Parathyroid hormone fragments and analogs The present invention relates to parathyroid hormone peptides and their use in the treatment of bone disorders. In particular, the invention relates to human parathyroid hormone peptide fragments and analogs that stimulate bone formation without the unwanted side effects associated with known parathyroid hormone peptides. Degenerative bone diseases, such as osteoporosis, are the most frequently occurring skeletal system diseases. It is characterized by an imbalance of cell biological activity between bone formation and bone resorption that results in loss of bone mass. The problems associated with the treatment of osteoporosis and conditions of reduced bone mass are widely unsolved. This is especially true in cases where there is a significant reduction in bone mass and reduced bone remodeling, as seen in the later stages of osteoporosis. Successful treatment must not only prevent the progression of the disease, but also stimulate new bone formation. Current treatments for osteoporosis include hormone therapy, calcium and vitamin D supplementation and sodium fluoride treatment, most of which are unsatisfactory. Bone loss can be delayed by such treatment, but the total net increase in bone mass is limited. It has sometimes been known that parathyroid hormone (PTH) regulates calcium and phosphorus metabolism and has a beneficial effect on bone metabolism. However, administration of PTH induces a fast proliferation of osteoclasts associated with bone destruction, as well as a slow stimulation of osteoblasts required for bone formation. The first 34 N-terminal amino acids of the 84 amino acids that make up PTH, (1-34) PTH, are responsible for almost all of the biological activity of its native hormone. Numerous clinical trials and experimental studies have shown that both PTH and (1-34) PTH have only very limited clinical value in the treatment of osteoporosis. This is because there is a small, inconsistent and unpredictable total increase in bone mass due to their stimulation of osteoclast activity and osteoblast activity. Moreover, continuous use of PTH or (1-34) PTH induces tachiphylaxis within 12-18 months after initiation of treatment. Removal of the first 1 or 2 amino acids is known to reduce the activity of PTH and (1-34) PTH associated with osteoclast stimulation and bone resorption in vitro. It has been suggested that parathyroid hormone fragment (3-34) PTH will stimulate osteoblast proliferation and bone formation without concomitant bone resorption. However, (3-34) PTH has similar antigenic activity and tachyphylaxis to (1-34) PTH, which causes unwanted antibody formation and resistance to therapy. All of the currently known PTH fragments and analogs have limited value in the treatment of osteoporosis due to their bone resorption activity, antigenicity or tachyphylaxis. Human parathyroid hormone fragments in which the C-terminal amino acid is amino acids 35-38, preferably 37 or 38, and at least the first N-terminal amino acid has been removed, as well as analogs and derivatives thereof, are unwanted levels. It has now been discovered that it stimulates osteoblastic activity and maximizes bone formation without bone resorption, antibody formation, or anaphylaxis in mice. The human parathyroid hormone fragment according to the present invention can be represented according to the standard nomenclature according to formula (mn) PTH, where m is the number of the first N-terminal amino acid, and the present invention Is at least 2 and n is amino acids 35-38. In preferred PTH fragments, analogs and derivatives, m is 2-28, and: a) (3-38) PTH, (4-38) PTH, (5-38) PTH, (6-38) PTH , (7-38) PTH, (8-38) PTH, (9-38) PTH, (10-38) PTH, (11-38) PTH, (12-38) PTH, (13-38) PTH, (14-38) PTH, (15-38) PTH, (16-38) PTH, (17-38) PTH, (18-38) PTH, (19-38) PTH, (20-38) PTH, (21-38) PTH, (22-38) PTH, (23-38) PTH, (24-38) PTH, (25-38) PTH, (26-38) PTH, (27-38) PTH or ( 28-38) PTH, especially (3-38) PTH; b) (3-37) PTH, (4-37) PTH, (5-37) PTH, (6-37) PTH, (7-37) PTH , (8-37) PTH, (9-37) PTH, (10-37) PTH, (11-37) PTH, (12-37) PTH, (13-37) PTH, (14-37) PTH, (15-37) PTH, (16-37) PTH, (17-37) PTH, (18-37) PTH, (19-37) PTH, (20-37) PTH, (21-37) PTH, (22-37) PTH, (23-37) PTH, (24-37) PTH, (25-37) PTH, (26-37) PTH, (27-37 PTH or (28-37) PTH, especially (3-37) PTH; c) (2-35) PTH, (2-36) PTH, (2-37) PTH or (2-38) PTH, especially (2 -37) PTH and (2-38) PTH; d) a), b) or c), [Tyr 34 ], [Nle 8.18 Tyr 34 ], [Phe 23 ], [Le u 23 ], [Nle 23 ] ], [Val 23 ], [Tyr 23 ], [alpha-naphthylalanine 23 ], or [beta-naphthylalanine 23 ] analog; or e) a), b), c) or d) a C-terminal amide derivative. , Where PTH is human parathyroid hormone (hPTH). }, Or a pharmaceutically acceptable salt or a hydrolyzable ester thereof. The compound according to the present invention is synthesized by a known technique, for example, a solid phase peptide synthesis method developed by Merrifield (“Solid Phase Peptide Synthesis”, Advances in Enzymolog y, 32: 221-296, 1969). The C-terminal amino acid of the peptide is covalently attached to the solid support via the carboxyl group. The desired peptide sequence is prepared by stepwise coupling a single amino acid in a protected form to the peptide chain growing from its carboxyl towards its amino terminus. The need for cumbersome strategies in this synthesis is minimized because each amino acid is joined by almost the same series of reactions. This method is fast; and after production of the desired peptide chain, the peptide can be easily deprotected by standard techniques, where appropriate. Alternatively, peptide fragments can be prepared using recombinant DNA technology. DNA for the desired peptide can be synthesized on a commercially available oligonucleotide synthesizer, eg, Applied Biosystem Inc. automated synthesizer, using the manufacturer's procedures. The DNA is then expressed in a conventional host, such as E. coli , yeast or mammalian cells using a suitable vector to produce the desired peptide fragment. The parathyroid hormone peptide as described above was shown in male or female rats weighing over 50 grams given a dose of peptide between 100 μg / kg body weight and 1000 μg / kg body weight per day. , Is useful in stimulating bone formation. The animals were divided into 5 groups of 12 animals each and received daily subcutaneous injections for up to 1 month. Group 1 is a placebo control; Group 2 receives 100 μg / kg / day standard (1-38) hPTH; Group 3 receives 100 μg / kg / day peptide; Group 4 400 μg / kg / day of peptide; and Group 5 receives 1000 μg / kg / day of peptide. For each group of animals, serum protein and enzyme levels that reflect changes in bone metabolism are assayed at the end of treatment (eg, serum osteocalcin, serum alkaline phosphatase, and serum tartrate-resistant acid phosphatase). All animals treated: (1) [ 3 H] -Tetracycline at 25 μCi / 100 g body weight to measure uptake of radioactivity into bone; or (2) Morphometric determination of mineral apposition / bone formation rates. Two injections of a tetracycline compound for fluorescently labeling newly mineralized cancellous bone for-either a first injection 4-5 days before killing and a second injection 1-2 days before killing , Receive the tetoracycline compound during the last week of. Animals are sacrificed at the end of treatment, and femurs, vertebrae, and tibiae for either radioisotope or morphometric analysis of cancellous and / or cortical bone and in bone extracts (eg, alkaline phosphatase and tartrate tolerance). Acid phosphatase) for analysis. The PTH hormone fragments, analogs and derivatives according to the present invention are therefore useful in the treatment of degenerative bone diseases, and a method of treating osteoporosis or hypercalcemia, which is a parathyroid hormone according to the present invention. -By providing a therapeutically effective dose of the peptide to a patient in need of such treatment. Further, the present invention is a method for treating hyperparathyroidism, particularly hypercalcemia, renal failure, or hyperparathyroidism that appears as hypertension, which is applied to a subject in need of such treatment. There is provided a method comprising administering a therapeutically effective amount of such parathyroid hormone. The present invention further provides methods for treating pathological conditions created by tumors or other abnormal cells that overproduce peptide hormone-like molecules, as well as the treatment of inflammation, allergic responses or immune disorders comprising hyperactive lymphocytes. A method is provided which comprises administering to a subject in need thereof a therapeutically effective amount of a peptide hormone fragment, analogue or derivative according to the present invention. The amount of parathyroid hormone peptide of the present invention administered for the above uses will vary depending on the peptide used and the subject undergoing treatment. However, satisfactory results are obtained when pebutide is administered daily or intermittently, and optionally for a 4-week or 6-week cycle, five to one to four week peptide-free periods. The peptides according to the invention may be administered to osteoporosis subjects or subjects with reduced bone mass, for example humans, in a dose range of 20-2000 μg / day, preferably 100-1000 μg / day. it can. It can be administered in a single dose or in several doses over 24 hours or as a continuous intravenous infusion. During or after treatment, all parameters of calcium metabolism that can be influenced by parathyroid peptides must be measured. Therefore, bone, intestinal and renal calcium metabolism and 1,25- (OH) 2 -vitamin D synthesis must be monitored to determine the efficacy of the treatment and possible metabolic side effects. The peptide of the present invention is administered enterally, parenterally, or subcutaneously in a mixture with a conventional pharmaceutical carrier. They are orally in the form of tablets or capsules or parenterally as solutions, eg sterile injectable solutions, suspensions, eg aqueous suspensions, or coated with the active ingredient by known techniques and disintegrating. And in a depot form that delays absorption and thereby provides a sustained action over a very long period of time. They can also be administered nasally in the form of sprays or rectally in the form of suppositories or enemas. They are preferably administered subcutaneously or rectally, and especially nasally. Because they do not stimulate bone resorption and cause erosion of nasal cartilage. Smaller PTH fragments with m of 18-28 are particularly useful for nasal administration. Because they are easily absorbed through the membrane of the nose. Pharmaceutical compositions according to the invention may be formulated as disclosed in the art and contain up to about 90% active ingredient in combination with the carrier or adjuvant. Example 1 (3-38) PTH Synthesis Parathyroid hormone fragment (3-38) PTH is synthesized by the Merri field solid phase method using a peptide synthesizer. A tert-butyloxycarbonyl (Boc) group is used to protect the alpha-amino group of each amino acid during coupling. Other functional side groups are protected as follows: (a) the hydroxyl group of serine is protected as its 0-benzyl ether; (b) the hydroxyl group of tyrosine is its 0-2,6-dichlorobenzyl ether. Or protected as a p-bromobenzyloxycarbonyl ester; (c) protected the carboxyl groups of glutamic acid and aspartic acid as its benzyl or cyclohexyl ester; (d) the imidazole nitrogen of histidine with a bezyloxymethyl (BOM) group. (E) the guanidine functional group of arginine is protected by its p-toluenesulfonyl group; and (f) the indole imine of tryptophan is protected by its formyl group. Peptide-resin synthesis is performed using the manufacturer's specific protocol for the synthesizer. After the synthesis is complete, the peptide is deprotected, cleaved from the copolymer resin and purified according to the manufacturer's protocol to give (3-38) PTH. Follow the steps above to get (2-35) PTH, (2-36) PTH, (2-37) PTH, (2-38) PTH, (4-38) PTH, (5-38) PTH, (6- 38) PTH, (7-38) PTH, (8-38) PTH, (9-38) PTH, (10-38) PTH, (11-38) PTH, (12-38) PTH, (13- 38) PTH, (14-38) PTH, (15-38) PTH, (16-38) PTH, (17-38) PTH, (18-38) PTH, (19-38) PTH, (20-38 ) PTH, (21-38) PTH, (22-38) PTH, (23-38) PTH, (24-38) PTH, (25-38) PTH, (26-38) PTH, (27-38) ) PTH, (28-38) PTH, (3-37) PTH, (4-37) PTH, (5-37) PTH, (6-37) PTH, (7-37) PTH, (8-37) PTH, (9-37) PTH, (10-37) PTH, (11-37) PTH, (12-37) PTH, (13-37) PTH, (14-37) PTH, (15-37) PTH, (16-37) PTH, (17-37) PTH, (18-37) PTH, (19-37) PTH, (20-37) PTH, (21-37) PTH, (22-37) PTH , (23-37) PTH, (24-37) PTH, (25-37) PTH, (26-37) PTH, (27-37) PTH, or (28-37) PTH are similarly synthesized.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 FI C07K 7/06 7/08 ─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. 6 Identification code Internal reference number FI C07K 7/06 7/08
Claims (1)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US92607092A | 1992-08-05 | 1992-08-05 | |
US07/926,070 | 1992-08-05 | ||
PCT/US1993/007375 WO1994003201A1 (en) | 1992-08-05 | 1993-08-05 | Parathyroid hormone fragments and analogs |
Publications (1)
Publication Number | Publication Date |
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JPH08503692A true JPH08503692A (en) | 1996-04-23 |
Family
ID=25452700
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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JP6505568A Pending JPH08503692A (en) | 1992-08-05 | 1993-08-05 | Parathyroid hormone fragments and analogs |
Country Status (4)
Country | Link |
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EP (1) | EP0656784A4 (en) |
JP (1) | JPH08503692A (en) |
CA (1) | CA2141588A1 (en) |
WO (1) | WO1994003201A1 (en) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5814603A (en) * | 1992-06-12 | 1998-09-29 | Affymax Technologies N.V. | Compounds with PTH activity |
DE4434551A1 (en) * | 1994-09-28 | 1996-04-04 | Forssmann Wolf Georg Prof Dr D | Peptides from the sequence of hPTH (1-37) |
AUPP794898A0 (en) * | 1998-12-24 | 1999-01-28 | Garvan Institute Of Medical Research | Transgenic animal |
US6689566B1 (en) | 1999-01-14 | 2004-02-10 | Scantibodies Laboratory, Inc. | Methods, kits, and antibodies for detecting parathyroid hormone |
US7820393B2 (en) | 1999-01-14 | 2010-10-26 | Scantibodies Laboratory, Inc. | Methods, kits and antibodies for detecting parathyroid hormone |
US6923968B2 (en) | 2000-08-10 | 2005-08-02 | Scantibodies Laboratory, Inc. | Cyclase inhibiting parathyroid hormone antagonists or modulators and osteoporosis |
WO2004028444A2 (en) | 1999-06-02 | 2004-04-08 | Scantibodies Laboratory, Inc. | Parathyroid hormone antagonists and uses thereof |
US7056655B2 (en) | 2001-11-02 | 2006-06-06 | Scantibodies Laboratory, Inc. | Methods for monitoring and guiding therapeutic suppression of parathyroid hormone in renal patients having secondary hyperparathyroidism |
US6524788B1 (en) | 2001-11-02 | 2003-02-25 | Thomas L. Cantor | Methods for monitoring and guiding therapeutic suppression of parathyroid hormone in renal patients having secondary hyperparathyroidism |
WO2003059291A2 (en) | 2002-01-10 | 2003-07-24 | Osteotrophin Llc | Treatment of bone disorders with skeletal anabolic drugs |
CN101355959B (en) | 2005-11-10 | 2013-02-27 | 密歇根理工大学管理委员会 | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
CA2782640A1 (en) | 2009-12-07 | 2011-06-16 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
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Publication number | Priority date | Publication date | Assignee | Title |
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US4086196A (en) * | 1975-03-28 | 1978-04-25 | Armour Pharmaceutical Company | Parathyroid hormone |
US4968669A (en) * | 1988-05-09 | 1990-11-06 | Merck & Co., Inc. | Parathyroid hormone antagonists |
DE4203040A1 (en) * | 1992-02-04 | 1993-08-05 | Boehringer Mannheim Gmbh | NEW PARATHORMON FRAGMENTS, THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM |
-
1993
- 1993-08-05 WO PCT/US1993/007375 patent/WO1994003201A1/en not_active Application Discontinuation
- 1993-08-05 CA CA002141588A patent/CA2141588A1/en not_active Abandoned
- 1993-08-05 EP EP93919895A patent/EP0656784A4/en not_active Withdrawn
- 1993-08-05 JP JP6505568A patent/JPH08503692A/en active Pending
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CA2141588A1 (en) | 1994-02-17 |
EP0656784A4 (en) | 1997-06-04 |
WO1994003201A1 (en) | 1994-02-17 |
EP0656784A1 (en) | 1995-06-14 |
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