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WO1994003201A1 - Fragments et analogues d'hormone parathyroidienne - Google Patents

Fragments et analogues d'hormone parathyroidienne Download PDF

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Publication number
WO1994003201A1
WO1994003201A1 PCT/US1993/007375 US9307375W WO9403201A1 WO 1994003201 A1 WO1994003201 A1 WO 1994003201A1 US 9307375 W US9307375 W US 9307375W WO 9403201 A1 WO9403201 A1 WO 9403201A1
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WO
WIPO (PCT)
Prior art keywords
pth
parathyroid hormone
subject
treatment
human parathyroid
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.)
Ceased
Application number
PCT/US1993/007375
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English (en)
Inventor
Sandra R. Hilliker
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Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to EP93919895A priority Critical patent/EP0656784A4/fr
Priority to JP6505568A priority patent/JPH08503692A/ja
Publication of WO1994003201A1 publication Critical patent/WO1994003201A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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

Definitions

  • This invention relates to parathyroid hormone peptides and their use in treating bone disease.
  • this invention relates to human parathyroid hormone peptide fragments and analogs which stimulate bone formation without the undesirable side effects associated with known parathyroid hormone peptides.
  • Degenerative bone disease such as osteoporosis
  • osteoporosis is the most frequently occurring disease of the skeletal system. It is characterized by an imbalance in cell biological activity between bone formation and bone resorption which results in a reduction of bone mass.
  • the problems involved ' in treating osteoporosis and conditions of reduced bone mass are largely unresolved. This is especially true in cases where a considerable reduction of bone mass has occurred and remodeling of the bone has decreased, as seen in the late stages of osteoporosis.
  • Successful treatment should not only prevent progression of the disease, but should also stimulate new bone formation.
  • Present treatment of osteoporosis includes hormone therapy, calcium and vitamin D supplements and sodium fluoride treatment, which for the most part are unsatisfactory.
  • Bone loss may be slowed down by such treatment, but the total net gain in bone mass is limited.
  • the parathyroid hormone (PTH) regulates calcium and phosphorus metabolism and has a potent effect on bone metabolism.
  • Administration of PTH induces a rapid proliferation of osteoclast cells associated with bone destruction, as well as a slower stimulation of osteoblast cells, which are necessary for bone formation.
  • the first 34 N-terminal amino acids, (1-34)PTH of the 84 amino acids, which make up PTH, are responsible for nearly all of the biological activity of the native hormone. Numerous clinical trials and experimental work have shown that both PTH and (1-34JPTH are only of very limited clinical value in treating osteoporosis.
  • human parathyroid hormone fragments in which the C-terminal amino acid is amino acid 35 to 38, preferably 37 or 38 and at least the first N-terminal amino acid has been removed, and analogs and derivatives thereof stimulate osteoblast activity and maximize bone formation without undesirable levels of bone resorption, antibody formation, or tachiphylaxis.
  • the human parathyroid hormone fragments of this invention can be represented in accordance with standard nomenclature by the formula (m-n)PTH, where is the number of the first N-terminal amino acid and is at least 2 in the present invention and n is amino acid 35 to 38.
  • ⁇ t is 2 to 28 and comprise;
  • (3-37)PTH (4-37JPTH, (5-37JPTH, (6-37JPTH, (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, (18-37JPTH, (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;
  • PTH is human parathyroid hormone (hPTH), or a pharmaceutically acceptable salt or hydrolysable ester thereof.
  • the compounds of the invention are prepared by the known techniques, for example, the solid-phase peptide synthesis developed by Merrified ("Solid Phase Peptide Synthesis", Advances in Enzymology, 32:221-296, 1969).
  • the C-terminal amino acid of the peptide is linked covalently via the carboxyl group to a solid support.
  • the desired peptide sequence is prepared by stepwise coupling of single amino acids in protected form, if necessary, to a peptide chain growing from the carboxyl toward the amino terminus. Because each amino acid is coupled by nearly the same series of reactions, the need for elaborate strategies in the synthesis is minimized. The method is rapid; and after preparation of the desired peptide chain, the peptide can be easily deprotected by standard techniques, where necessary.
  • the peptide fragment can be prepared using recombinant DNA technology.
  • the DNA for the desired peptide can be synthesized with a commercially available oligonucleotide synthesizer (gene machine), such as Applied Biosyste Inc. automated synthesizer, using the manufacturer's procedure.
  • the DNA is then expressed using a suitable vector in a conventional host, such as E coli ' , yeast or a mam alion cell to yield the desired peptide fragment.
  • the above parathyroid hormone peptides are- useful in stimulating bone formation as indicated in male or female rats weighing more than 50 grams given doses of peptide between 100 ug/kg body weight and 1000 ug/kg body weight per day.
  • the animals are divided into five groups of 12 animals each and given subcutaneous injections daily for up to one month.
  • Group 1 is the placebo control;
  • group 2 receives 100 ug/kg/day of the standard (l-38)hPTH;
  • group 3 receives 100 ug/kg/day of peptide;
  • group 4 receives 400 ug/kg/day of peptide; and
  • group 5 receives 1000 ug/kg/day of peptide.
  • the levels of serum proteins and enzymes which reflect changes in bone metabolism are assayed at the end of treatment (e.g. serum osteocalcin, serum alkaline phosphatase, and serum tartrate resistant acid phosphatase) .
  • All animals receive tetracycline compounds during the last week of treatment: (1) either [ 3 H]-tetra ⁇ cycline at 25 uCi/100 g body weight to measure radioisotope incorporation into bone; or (2) two injections of tetra ⁇ cycline compounds - the first injection four to five days before sacrifice and the second injection one to two days before sacrifice - to fluorescently label newly mineralizing cancellous bone for the measurement of mineral apposition rate/bone formation rate by morphometry.
  • Animals are sacrificed at the end of treatment and femurs, vertebrae, and tibias collected for either radioisotopic or morphometric analysis of cancellous and/or cortical bone and for the analysis of bone extracts (e.g. alkaline phosphatase and tartrate resistant acid phosphatase).
  • bone extracts e.g. alkaline phosphatase and tartrate resistant acid phosphatase.
  • the PTH hormone fragments, analogs, and derivatives of this invention are therefore useful in treating 1 degenerative bone disease and provide a method of treating osteoporosis or hypercalcemia through the administration of a therapeutically effective amount of a parathyroid hormone peptide of the invention to a subject in need of said treatment.
  • the invention provides a method of treating hyperparathyroidi ⁇ m, in particular, hyperparathyroidism expressed as a hypercalcemic crisis, renal failure, or hypertension, which comprises administering to a subject in need of said treatment a therapeutically effective amount of a parathyroid hormone peptide of the invention.
  • This invention further provides a method of treating the disease state produced by a tumor or other aberrant cell overproducing a peptide hormone-like molecule and a method of treating immune diseases wherein the disease state comprises inflammation, an allergic response, or hyperactive lymphocytes comprising the administration of a therapeutically effective amount of a peptide hormone fragment, analog, or derivative of the present invention to a subject in need of said treatment.
  • the amount of parathyroid hormone peptide of the invention administered for the above uses will vary depending on the peptide used and the subject undergoing treatment. However, satisfactory results are obtained when the peptide is administered daily or intermittently, and, if desirable, in- 4-week or 6-week cycles followed by peptide free periods of 1 to 4 weeks.
  • the peptides of the invention may be administered, in particular, to osteoporotic subjects or those with reduced bone mass, e.g., humans, in a dosage range of 20-2000 ⁇ g/day, preferably 100-1000 ⁇ g/day. It may be administered in a single dose or in several doses over 24 hours or as a continuous intravenous infusion.
  • the peptides of the invention are administered enterally, parenterally, or subcutaneously admixed with conventional pharmaceutical carriers. They may be administered orally in the form of tablets or capsules or parenterally as solutions, e.g., sterile injectable solution, suspensions, e.g., aqueous suspension, or in depot form, in which the active ingredient is coated by known techniques to delay disintegration and absorption and thereby provide a sustained action over large periods of time.' They may 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, since they do not stimulate bone resorption and cause erosion of the nasal cartilage.
  • the smaller PTH fragments in which m is 18 to 28 are particularly useful for nasal administration, because they are more readily absorbed through the nasal membrane.
  • the pharmaceutical compositions of the invention are formulated as disclosed in the art and may contain up to about 90% of the active ingredients in combination with the carrier or adjuvant.
  • parathyroid hormone fragment (3-38) PTH is carried out by the solid phase method of Merrifield using a peptide synthesizer.
  • Tertiary butyloxycarbonyl (Boc) group is used to protect the al-pha-amino group of each amino acid during coupling.
  • the peptide-resin synthesis is carried out using the synthesizer manufacturer's specified protocols. After synthesis is complete, the peptide is deprotected, cleaved from the copoly er resin, and purified in accordance with the manufacturer's protocol to yield (3-38)PTH.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Fragment d'hormone parathyroïdienne humaine dans lequel l'acide aminé C-terminal est de l'acide aminé 35 à 38 et au moins le premier acide aminé N-terminal a été enlevé, ou analogue ou dérivé de ladite hormone, ou sel ou ester hydrolysable pharmaceutiquement acceptables de ceux-ci, et leur utilisation dans le traitement de maladies osseuses dégénératives.
PCT/US1993/007375 1992-08-05 1993-08-05 Fragments et analogues d'hormone parathyroidienne Ceased WO1994003201A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP93919895A EP0656784A4 (fr) 1992-08-05 1993-08-05 Fragments et analogues d'hormone parathyroidienne.
JP6505568A JPH08503692A (ja) 1992-08-05 1993-08-05 上皮小体ホルモン断片及びアナログ

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US92607092A 1992-08-05 1992-08-05
US07/926,070 1992-08-05

Publications (1)

Publication Number Publication Date
WO1994003201A1 true WO1994003201A1 (fr) 1994-02-17

Family

ID=25452700

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/007375 Ceased WO1994003201A1 (fr) 1992-08-05 1993-08-05 Fragments et analogues d'hormone parathyroidienne

Country Status (4)

Country Link
EP (1) EP0656784A4 (fr)
JP (1) JPH08503692A (fr)
CA (1) CA2141588A1 (fr)
WO (1) WO1994003201A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4434551A1 (de) * 1994-09-28 1996-04-04 Forssmann Wolf Georg Prof Dr D Peptide aus der Sequenz des hPTH (1-37)
US5814603A (en) * 1992-06-12 1998-09-29 Affymax Technologies N.V. Compounds with PTH activity
WO2000038707A1 (fr) * 1998-12-24 2000-07-06 Garvan Institute Of Medical Research Methode de traitement de la perte osseuse
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
US6689566B1 (en) 1999-01-14 2004-02-10 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
US7015195B2 (en) 2002-01-10 2006-03-21 Osteotrophin, Llc Treatment of bone disorders with skeletal anabolic drugs
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
US7820393B2 (en) 1999-01-14 2010-10-26 Scantibodies Laboratory, Inc. Methods, kits and antibodies for detecting parathyroid hormone
US7893021B2 (en) 1999-06-02 2011-02-22 Scantibodies Laboratory, Inc. Parathyroid hormone antagonists and uses thereof
US7994129B2 (en) 2005-11-10 2011-08-09 Michigan Technological University Methods of using black bear parathyroid hormone
US8987201B2 (en) 2009-12-07 2015-03-24 Michigan Technological University Black bear parathyroid hormone and methods of using black bear parathyroid hormone

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4203040A1 (de) * 1992-02-04 1993-08-05 Boehringer Mannheim Gmbh Neue parathormonfragmente, deren herstellung und diese enthaltende arzneimittel

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0656784A4 *

Cited By (20)

* Cited by examiner, † Cited by third party
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 (de) * 1994-09-28 1996-04-04 Forssmann Wolf Georg Prof Dr D Peptide aus der Sequenz des hPTH (1-37)
WO1996010041A1 (fr) * 1994-09-28 1996-04-04 Forssmann Wolf Georg PEPTIDES DE LA SEQUENCE DE hPTH (1-37)
WO2000038707A1 (fr) * 1998-12-24 2000-07-06 Garvan Institute Of Medical Research Methode de traitement de la perte osseuse
US7943323B2 (en) 1999-01-14 2011-05-17 Scantibodies Laboratory, Inc. Methods for differentiating and monitoring parathyroid and bone status related diseases
US7892749B2 (en) 1999-01-14 2011-02-22 Scantibodies Laboratory, Inc. Methods for differentiating and monitoring parathyroid and bone status related diseases
US6743590B1 (en) 1999-01-14 2004-06-01 Scantibodies Laboratory, Inc. Methods for differentiating and monitoring parathyroid and bone status related diseases
US8329409B2 (en) 1999-01-14 2012-12-11 Scantibodies Laboratory, Inc. Methods, kits, and antibodies for detecting parathyroid hormone
US8298770B2 (en) 1999-01-14 2012-10-30 Scantibodies Laboratory, Inc. Methods, kits, and antibodies for detecting parathyroid hormone
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
US7723042B2 (en) 1999-01-14 2010-05-25 Scantibodies Laboratory, Inc. Methods for differentiating and monitoring parathyroid and bone status related diseases
US7893021B2 (en) 1999-06-02 2011-02-22 Scantibodies Laboratory, Inc. Parathyroid hormone antagonists and uses thereof
US6923968B2 (en) 2000-08-10 2005-08-02 Scantibodies Laboratory, Inc. Cyclase inhibiting parathyroid hormone antagonists or modulators and osteoporosis
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
US7384912B2 (en) 2002-01-10 2008-06-10 Osteotrophin, Llc Treatment of bone disorders with skeletal anabolic drugs
US7015195B2 (en) 2002-01-10 2006-03-21 Osteotrophin, Llc Treatment of bone disorders with skeletal anabolic drugs
US7994129B2 (en) 2005-11-10 2011-08-09 Michigan Technological University Methods of using black bear parathyroid hormone
US8987201B2 (en) 2009-12-07 2015-03-24 Michigan Technological University Black bear parathyroid hormone and methods of using black bear parathyroid hormone

Also Published As

Publication number Publication date
JPH08503692A (ja) 1996-04-23
EP0656784A1 (fr) 1995-06-14
EP0656784A4 (fr) 1997-06-04
CA2141588A1 (fr) 1994-02-17

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