WO1993006846A1 - Parathyroid hormone analogues and use in osteoporosis treatment - Google Patents
Parathyroid hormone analogues and use in osteoporosis treatment Download PDFInfo
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- WO1993006846A1 WO1993006846A1 PCT/US1992/008478 US9208478W WO9306846A1 WO 1993006846 A1 WO1993006846 A1 WO 1993006846A1 US 9208478 W US9208478 W US 9208478W WO 9306846 A1 WO9306846 A1 WO 9306846A1
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- parathyroid hormone
- structure shown
- hormone analogue
- leu
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Classifications
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- 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 (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
Definitions
- PTH Parathyroid hormone
- PTH is a polypeptide and the amino acid seguences of bovine and human PTH are closely related. Only the residues at locations one, seven and sixteen differ between the two. Synthetic polypeptides containing the first thirty-
- PTII 20 four residues of PTII may be prepared using the method disclosed by Erickson and Merrifield, The Proteins. Neurath et al. , Eds. , Academic Tress, New York, 197G, page 257, preferably as modified by the method of Hodges et al., Peptide Research, 1, 19 (1988).
- the antagonist of PTH is calcitonin, which acts to reduce
- Intracellular calcium has been shown to affect changes in vascular tension, as can be measured by changes in blood pressure.
- U.S. Patent Application 603,745 describes one method which has been discovered to regulate calcium uptake in vascular cells.
- Osteoporosis is a progressive disease which is particularly characteristic of post enopausal women, and results in the reduction of total bone mass. The sequelae frequently involve fractures of load-bearing bones and the physical degenerations characteristic of immobilizing injuries. Osteoporosis is associated with hyperthyroidi ⁇ m, hyp ⁇ rparathyroidism, Cushings syndrome and the use of certain steroidal drugs. Remedies historically have involved increase in dietary calcium, estrogen therapy and increased doses of vitamin D.
- PTH has been used to treat osteoporosis.
- PTII may exhibit oth ⁇ r undesired pharmalogical effects, sucli as hypotension and smooth muscle relaxation (e.g. relaxation of gastrointestinal organs, utorus?, tracheal and vas deferens) ⁇ s well ar, posi ivo chronotropic and inotropic effects on the heart.
- smooth muscle relaxation e.g. relaxation of gastrointestinal organs, utorus?, tracheal and vas deferens
- the relaxation effects of PTH on smooth muscle as well as positive chronotropic and inotropic effects of PTH are described in Pang et al, Trends in Pharmacological Sciences. Vol. 7, No. 9, pp. 340-341 (September 198G) .
- U.S. Patent No. 4,771,124 discloses the property of bovine and human PTH analogues wherein Trp is substituted by amino acids phenylalanine, leucine, norleucine, valine, tyrosine, beta-naphtylalanine and alpha-naphtylalanine as a PTH antagonist. While it was suggested that these analogues might be useful in the treatment of osteoporosis, it was based on the analogues antagonistic action to PTII. Furthermore, there was no data to indicate the effectiveness these analogues on bone or other tissue.
- analogues with substituted at Trp 23 with leucine, phenylalanine or tyrosine would produce undesired secondary effects of smooth muscle relaxation, vascular smooth muscle calcium change as well as positive t ⁇ chronotropic and inotropic effects on the heart.
- Fig. lb shows the structure of natural human PTH (SEQ ID NO:2) .
- Fig. 2a shows the structure of bPTH (1-34) with position 23 substituted with Xaa (SEQ ID NO:3).
- Figs. 2b-2p show the structure of bPTH (1-34) with position 23 substituted with Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, Ile, Lys, Met, Pro, Ser or Thr, respectively (SEQ ID NO:4 - SEQ ID NO:18) .
- Fig. 3a shows the structure of hPTH (1-34) with position
- Fig. 5 shows the structure of hPTH with position 23 substituted with Xaa (SEQ ID NO:36).
- Fig. 6 shows the effect of bPTH-(l-34) and its analogues on diastolic blood pressure of anestlietized Sprague-Dawley rats. Csll4 had no effect.
- Fig. 7 shows the effect of bPTH-(l-34) and its analogues on systolic blood pressure of anesthetized Sprague-Dawley rats. Csll4 had no effect.
- Fig. 8 shows the vasorelaxing effect of bPTH-(l-34) and its analogues on rat tail artery helical strip in vitro. Csll4 had no effect.
- Figs. 11 a-c show the depolarizing concentrations of KCl increasing calcium ion levels in cultured osteoblasts. Csll4 inhibits the KCl effect.
- Fig. 12 shows the relation between the relaxation curves of Sprague-Dawley rat tail artery helical strips, precontracted with AVP when treated with Csll4, Csll7 and Cs201.
- Fig. 13 shows the effects illustrated in. Fig. 12, using
- Fig. 16 shows the effect of Csll4 on the intracellular calcium concentration in the presence of KCl in UMR cells in culture.
- Fig. 17 shows a comparison of the effect of Cs205 and bPTH on the mean arterial blood pressure of anesthetized Sprague- Dawley rats.
- Fig. 18 shows the dose-response relationship between Cs205 and the tension of rat tail artery helical strips precontracted with KCl, norepinephrine and AVP.
- Fig. 19 shows a comparison of the effect of Cs201 and bPTH on the mean arterial blood pressure of anesthetized Sprague- Dawley rats.
- Fig. 20 shows the dose-response relationship between Cs201 and the tension of rat tail artery helical strips precontracted with KCl, norepinephrine and AVP.
- Fig. 21 shows a comparison of the effect of Cs503 and bPTH on the mean arterial blood pressure of anesthetized Sprague- Dawley rats.
- Fig. 25 shows a comparison of the effect of Cs501 and bPTH on the mean arterial blood pressure of anesthetized Sprague- Dawley rats.
- Fig. 28 shows the dose-response relationship between Cs207 and the tension of rat tail artery helical strips precontracted with KCl, norepinephrine and AVP.
- Fig. 29 shows the effect of Cs207 on intracellular calcium increase stimulated by KCl in cultured UMR osteoblast cells.
- Fig. 40 shows the effect of Csll4 (B) on intracellular calcium concentration stimulated by KCl in cultured UMR cells at 30 mM KCl.
- Fig. 41 shows the effect of Cs88 [bPTH-(l-34) ] on the mean arterial blood pressure of anesthetized Sprague-Dawley rats.
- Fig. 44 shows the effect of Cs88 on intracellular calcium concentration stimulated by KCl in cultured UMR cells.
- Fig. 46 shows the effect of Cs501 on the intracellular calcium concentration stimulated by KCl in the presence of KCl in UMR cells in culture.
- Fig. 47 shows the effect of CslOOl on the intracellular calcium concentration stimulated by KCl in the presence of KCl in UMR cells in culture.
- Fig. 48 shows the effect of Csll4 on the contractility and contraction rate of right atriai tissue of Sprague-Dawley rats.
- Fig. 49 shows the effect of Cs201 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 50 shows the effect of Cs205 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 51 shows the effect of Cs206 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 52 shows the effect of Cs207 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 53 shows the effect of Cs208 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 50 shows the effect of Cs205 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 51 shows the effect of Cs206 on the contractility and contraction rate of right atrial tissue of Sprague-Daw
- Fig. 54 shows the effect of Cs209 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 55 shows the effect of Cs211 on the contractility and contrnction rate of right atrial. tissue of Sprague-Dawley rats.
- Fig. 56 shows the effect of Cs212 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 57 shows the effect of Cs213 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 58 shows the effect of Cs214 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 59 shows the effect of Cs215 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 60 shows the effect of Cs220 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 61 shows the effect of Cs501 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 62 shows the effect of Cs503 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley ratr,
- Fig. 63 shows the effect of Cs2001 and CslOOl on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 64 shows the effect of Cs219 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 65 shows the effect of Cs218 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- Fig. 66 shows the effect of Cs502 on the contractility and contraction rate of right atrial tissue of Sprague-Dawley rats.
- PTH PTH
- Ca2+ calcium uptake from the gastrointestinal tract and the deposition and removal of calcium from bone.
- Calcium also has been found to be effective in the maintenance of blood pressure.
- Control of calcium in the walls of blood vessels is a useful therapeutic regimen for controlling hypertension and calcium channel blockers, which prevent the introduction of calcium into cell walls, is a conventional therapy for hypertension. Needleman et al. in Goodman and Gil an's The Pharmacological Basis of Therapeutics. MacMillan, New York, (1985), page 816 ff.
- Therapeutic dosages of PTH will, in some individuals, result in unacceptable diminution of blood pressure and may result in relaxation of smooth muscles such as gastrointestinal, uterus, tracheal, vas deferens as well as exhibit positive chronotropic and inotropic effects on the heart.
- smooth muscle relaxation effects and positive chronotropic and inotropic effects on the heart it was envisaged that the structure of PTH could be modified to decouple the hypotensive, smooth muscle relaxation and positive chronotropic and inotropic function from the bond calcium and bone deposition function.
- Trp tryptophane
- the * procedure of Erickson and Merrifield, as modified by Hodges et al.. as described above, may be used to synthesize synthetic PTH or fragments thereof.
- the procedure enables substitution for the naturally occurring PTH at substantially every location and it is possible to prepare both bovine and human synthetic PTH at full length or in the sequence of the first thirty-four amino acids, which is .more facilely performed. Such substitution can also be accomplished by genetic engineering.
- Substitution at position twenty-three invariably alters the observed hypotensive, smooth muscle relaxation and positive chronotropic and inotropic effects, whether the full length PTH or the 1-34 fragment is administered.
- Substitution of Ala for Trp at position twenty-three is particularly preferred because the change in blood pressure, smooth muscle relaxation and positive chronotropic and inotropic effects from this substitution are minimal and calcium uptake, as measured in osteoblasts, mimics the results from the administration of native PTH.
- the 1-34 PTH fragment with Ala 23 or other amino acids is particularly preferred because the pharmacological properties are those which are desired and the difficulty of synthesis is minimized. Synthesis of the compounds used in the development of this invention was performed at Alberta Peptide Institute (API) and the cooperation of API is gratefully acknowledged.
- bovine parathyroid hormone bPTH
- human parathyroid hormone hPTH
- Representative synthetic analogues are described in Table 1 and are further shown in Figs. 2-5 and SEQ ID N0:3-SEQ ID NO:36.
- the hypotensive effects of these analogues is shown in Figs. 6, 7, 17, 19, 21, 23, 25, 27, 31, 35, 36, and 41. All of the analogues produce either no or less diminution of blood pressure than does native PTH.
- the Ala 23 analogue provides almost no change in blood pressure, either systolic or diastolic, over a range of 0-5 ⁇ g/kg. At the level of 5 ⁇ g/kg of PTH, the blood pressure in Sprague-Dawley rats is such that they are essentially moribund.
- the strips may be precontracted using other pressor substances such as norepinephrine (NE) or KCl.
- NE norepinephrine
- KCl KCl
- osteoporosis is a progressive syndrome, a model is required and the use of cultured osteoblasts of the UMR-106 rat osteosarcoma cells, ATCC CRL 1661 have been used as the model.
- Intracellular calcium concentration change in these cells has been monitored using the FURA-2 method, wherein a fluorescent dye which is specific for calcium is used as a marker for calcium uptake into the cells.
- Cells are incubated with 1-10 ⁇ M of the acetomethoxy ester of FURA-2 for 30-60 minutes. Upon uptake, the ester is hydrolyzed to release free FUR ⁇ -2, which selectively binds free Ca + .
- FUR ⁇ -2 has a characteristic fluorescence spectrum, which wavelength is shifted when the dye binds to free Ca 2+ .
- Ca 2+ which is present in the cell can be quantified by exciting the dye at two different wavelengths, 340 and 380 nm.
- the emission fluorescence is measured at 510 nm.
- the calcium concentration is proportional to the ratio of the fluorescent emission when excited at 340 nm to the emission at 380 nm. It is conventional to report the concentration of calcium within the cell in terms of the fluorescence ratio, the 340/380 ratio. This technique is described in Grynkiewicz et al. , J. Biol. Chem. , 260, 3440 (1985) and Pang et al., P. N. A. S. (USA) , 87, 623 (1990) .
- Figs. 9, 10 a-d, 11 a-c, 16, 29, 30, 33, 34, 38, 39, 40, 43, 44 and 45-47 illustrate the results of the above-described measurements when inhibitors such as an anti-osteoporotic agent (788) or bPTH-(l-34) or Csll4 were used in the presence of KCl.
- inhibitors such as an anti-osteoporotic agent (788) or bPTH-(l-34) or Csll4 were used in the presence of KCl.
- the PTH analogues whether full length or 1-34, which contain anomalous amino acids at position twenty-three (most particularly those which contain Ala 23 ) do not effect a hypotensive and smooth muscle relaxation response, including positive chronotropic effects, but do inhibit calcium uptake as stimulated by KCl in osteoblasts, which indicates that these compounds would have the same effect on bone cells as PTH and would be useful in the treatment of osteoporosis in mammals and, particularly, in man, without the aformentioned deleterious side effects in the elderly-
- Trp 23 is substituted by other amino acids in 1-84 PTH and in the 1-34 analogues.
- the effect on KCl induced in osteoblasts is essentially unchanged for 1-84 or 1-34 PTH.
- the effect on bone cells is unchanged from PTH.
- the physiological significance of an inhibiting effect on the KCL induced calcium uptake in bone cells is not yet understood.
- the analogues interact fully with bone cell receptor activity. The fact that the same effect is seen for both PTH and the analogues disclosed herein suggests that the site of interaction with the osteoblast cell receptor is unchanged by the substitution.
- the analogues of trie present invention can be used in the 5 treatment of osteoporosis and other bone related diseases and disorders involving bone cell calcium regulation.
- the analogues of the present invention may be administered to a warm-blooded mammalian in need thereof, particularly a human, by parental, topical, rectal administration or by
- the analogues may be conventionally formulated in a parenteral dosage form compounding about 1 to about 300 mg per unit of dosage with a conventional vehicle, excipient, binder, preservative, stabilizer, color, agent or the like as called for by accepted pharmaceutical practice.
- a 1 to 10 ml intravenous, intramuscular or subcutaneous injection would be given one to four times daily.
- the injection would contain an analogue of the present invention in an aqueous isotonic sterile solution or suspension optionally with a preservative such as phenol or 0 a solubilizing agent such as ethylenediaminetetraacetic acid (EDT ⁇ ) .
- Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium. 5 Synthetic monoglycerides, diglycerides, fatty acids (such as oleic acid) find use as fixed oil in the preparation of in ectables.
- the analogues of the present invention can be prepared in the form of suppositories by 0 mixing with a suitable non-irritating excipient such as cocoa butter or polyethylene glycols.
- the analogues of the present invention can be prepared in the form of ointments, jellies, solutions, suspensions or dermal adhesive patches. 5
- analogues of the present invention may be administered by a spinhaler turbo-inhaler device obtained from Fisons Corporation of Bedford, Massachusetts, at a rate of about 0.1 to 50 mg per capsule, 1 to 8 capsules being administered daily for an average human.
- the compounds of the present invention are administered at the rate of about 100 to 1000 micrograms per "puff" or activated release of a standard volume of propellant.
- the liquid aerosol would be given at the rate of 1 to 8 "puffs" per day with variation in dosages due to the severity of the conditions being treated, the weight of the patient and the particle size distribution of the aerosol.
- a fluorinated hydrocarbon or isobutane find use as propellants for liquid aerosols.
- Daily doses are in the range of about 0.01 to about 200 mg per kg of body weight, depending on the activity of the specific compound, the age, weight, sex and conditions of the subject to be treated, the type and severity of the disease, the frequency and route of administration.
- the amount of active ingredient that may be combined with the carried materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration.
- the following examples demonstrate the utility of applicants' invention. The examples are not limiting, but are illustrative only, and modifications which would be apparent to those skilled in the art are included within the scope of this disclosure.
- Sprague-Dawley (S-D) rats were anaesthetized with pentobarbital and a cannula was inserted into the carotid artery. The rats were kept sedated during the procedure and were injected with PTH peptides only when the blood pressure of the rats were stable. Peptides were injected through a cannula in the jugular vein, in amounts of 1, 3 and 5 or more ⁇ g/kg and the mean systolic and diastolic blood pressure was monitored continuously throughout the procedure. Results are reported with comparison to bPTH-(l-34) .
- the assay was performed according to Pang et al. , Blood Vessels, 22, 57 (1985) .
- Sprague-Dawley rats were anaesthetized with pentobarbital and the tail artery excised and placed in ice-cold Krebs-Hanseleit solution (KHS) oxygenated with 95% 0 2 , 5% C0 2 -
- KHS Krebs-Hanseleit solution
- Each artery was cut helically and strips of approximately 1.5 cm were secured in a Sawyer-Bartlestone chamber containing KHS.
- the force generated by the strips was measured with a Grass FT03 force displacement transducer and recorded on a polygraph. Isolated tail artery helical strips were equilibrated for 1 hour prior to use.
- the solution was continously aerated by a gas mixture of 95% 0 2 -5% C0 2 .
- the right atrium was isolated and suspended in a tissue chamber containing 20 mL of PSS at 37°C, pH 7.4. Atria were allowed to equilibrate for 1 hr under a resting tension of 1 g.
- the atrial rate and force were determined from contractions recorded by a Grass FT.03 force-displacement transducer and a Grass model 79 polygraph.
- Dose-response curves for the peptides were obtained by cumulative addition of the respective peptides. Drug dose is calculated on the basis of the final concentration in the bath solution.
- Intracellular free calcium concentration was measured using the fluorescent dye FURA-2 according to the method of Grynkiewicz et al., J. Biol. Chem.. 260, 3440 (1985) and Pang et al., P. N. A. S. (USA) . 87, 623 (1990) .
- UMR-106 rat osteosarcoma cells (ATCC CRL-1661) are incubated in 1-10 ⁇ M FURA-2 AM (Sigma Chemical Co., St. Louis), the acetomethoxy ester of FURA-2.
- FUR ⁇ -2 Upon hydrolysis within the cell, FUR ⁇ -2 is released which selectively binds to free Ca 2+ . Binding to Ca 2+ shifts the fluorescent spectrum of FUR ⁇ -2.
- Quantitation is obtained by exciting the dye at two different wavelengths, preferably 340 and 380 nm and measuring the fluorescent emission at 510 nm.
- concentration of calcium is proportional to the ratio of the fluorescence emitted at 340 nm to that at 380 nm.
- KCl is used in the medium to stimulate Ca 2" ' " uptake. After the intracellular [Ca 2 ] ⁇ had been measured, the cells were washed with the original medium and the analogues added and the intracellular [Ca 2+ ] ⁇ measured again. KCl was then added without washing to measure the effect of the analogue on KCl induced Ca 2+ uptake. After measurement, the cells were washed with the medium 3-4 times and KCl again added to determine the recovery of the cells after removal of the analogue. Resu_ts are shown by actual traces and histograms summarizing the results. As can be seen from Figs. 10 a-d, PTII inhibits Ca 2+ uptake as measured by the method. Figs.
- MOLECULE TYPE protein
- MOLECULE TYPE peptide
- SEQUENCE DESCRIPTION SEQ ID NO:25:
- MOLECULE TYPE peptide
- SEQUENCE DESCRIPTION SEQ ID NO:30:
- MOLECULE TYPE protein
Abstract
Description
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US77309791A | 1991-10-10 | 1991-10-10 | |
US773,097 | 1991-10-10 |
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WO1993006846A1 true WO1993006846A1 (en) | 1993-04-15 |
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PCT/US1992/008478 WO1993006846A1 (en) | 1991-10-10 | 1992-10-09 | Parathyroid hormone analogues and use in osteoporosis treatment |
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WO (1) | WO1993006846A1 (en) |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996040775A1 (en) * | 1995-06-07 | 1996-12-19 | Syntex (U.S.A.) Inc. | Method for the treatment of corticosteroid induced osteopenia |
EP0847278A1 (en) * | 1995-07-13 | 1998-06-17 | Biomeasure, Inc. | Analogs of parathyroid hormone |
US5955574A (en) * | 1995-07-13 | 1999-09-21 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A. | Analogs of parathyroid hormone |
US5969095A (en) * | 1995-07-13 | 1999-10-19 | Biomeasure, Inc. | Analogs of parathyroid hormone |
US6025467A (en) * | 1995-06-15 | 2000-02-15 | Takeda Chemical Industries, Ltd. | Parathyroid hormone derivatives and their use |
US6544949B1 (en) | 1995-07-13 | 2003-04-08 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Analogs of parathyroid hormone |
EP1567178A1 (en) * | 2002-11-01 | 2005-08-31 | Amgen, Inc. | Modulators of receptors for parathyrois hormone and parathyroid hormone-related protein |
US7015195B2 (en) | 2002-01-10 | 2006-03-21 | Osteotrophin, Llc | Treatment of bone disorders with skeletal anabolic drugs |
US7410948B2 (en) | 1995-07-13 | 2008-08-12 | Societe De Conseils De Recherches Et D'applications Scientifiques, Sas | Analogs of parathyroid hormone |
WO2008019062A3 (en) * | 2006-08-04 | 2009-04-09 | Gen Hospital Corp | Polypeptide derivatives of parathyroid hormone (pth) |
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 |
US9057727B2 (en) | 2007-08-01 | 2015-06-16 | The General Hospital Corporation | Screening methods using G-protein coupled receptors and related compositions |
US9492508B2 (en) | 2010-05-13 | 2016-11-15 | The General Hospital Corporation | Parathyroid hormone analogs and uses thereof |
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US4086196A (en) * | 1975-03-28 | 1978-04-25 | Armour Pharmaceutical Company | Parathyroid hormone |
US4771124A (en) * | 1987-05-26 | 1988-09-13 | Merck & Co., Inc. | Parathyroid hormone antagonists with simplified synthetic methodology |
US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
-
1992
- 1992-10-09 WO PCT/US1992/008478 patent/WO1993006846A1/en active Application Filing
- 1992-10-09 AU AU28078/92A patent/AU2807892A/en not_active Abandoned
Patent Citations (3)
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 |
US4833125A (en) * | 1986-12-05 | 1989-05-23 | The General Hospital Corporation | Method of increasing bone mass |
US4771124A (en) * | 1987-05-26 | 1988-09-13 | Merck & Co., Inc. | Parathyroid hormone antagonists with simplified synthetic methodology |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996040775A1 (en) * | 1995-06-07 | 1996-12-19 | Syntex (U.S.A.) Inc. | Method for the treatment of corticosteroid induced osteopenia |
JP2008024709A (en) * | 1995-06-07 | 2008-02-07 | Syntex Usa Inc | Method for the treatment of corticosteroid induced osteopenia |
US6025467A (en) * | 1995-06-15 | 2000-02-15 | Takeda Chemical Industries, Ltd. | Parathyroid hormone derivatives and their use |
USRE40850E1 (en) | 1995-07-13 | 2009-07-14 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Analogs of parathyroid hormone |
US5969095A (en) * | 1995-07-13 | 1999-10-19 | Biomeasure, Inc. | Analogs of parathyroid hormone |
EP0847278A4 (en) * | 1995-07-13 | 1999-01-13 | Biomeasure Inc | 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 |
US6921750B2 (en) | 1995-07-13 | 2005-07-26 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Analogs of parathyroid hormone |
US5955574A (en) * | 1995-07-13 | 1999-09-21 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A. | Analogs of parathyroid hormone |
EP0847278A1 (en) * | 1995-07-13 | 1998-06-17 | Biomeasure, Inc. | Analogs of parathyroid hormone |
US7410948B2 (en) | 1995-07-13 | 2008-08-12 | Societe De Conseils De Recherches Et D'applications Scientifiques, Sas | Analogs of parathyroid hormone |
CN100412091C (en) * | 1995-07-13 | 2008-08-20 | 提议和科学执行公司 | Analogs of parathyroid hormone |
US7632811B2 (en) | 1995-07-13 | 2009-12-15 | Societe De Conseils De Recherches Et D'applications Scientifiques, Sas | Analogs of parathyroid hormone |
US7015195B2 (en) | 2002-01-10 | 2006-03-21 | Osteotrophin, Llc | Treatment of bone disorders with skeletal anabolic drugs |
US7384912B2 (en) | 2002-01-10 | 2008-06-10 | Osteotrophin, Llc | Treatment of bone disorders with skeletal anabolic drugs |
EP1567178A1 (en) * | 2002-11-01 | 2005-08-31 | Amgen, Inc. | Modulators of receptors for parathyrois hormone and parathyroid hormone-related protein |
EP1567178A4 (en) * | 2002-11-01 | 2009-07-15 | Amgen Inc | Modulators of receptors for parathyrois hormone and parathyroid hormone-related protein |
US7994129B2 (en) | 2005-11-10 | 2011-08-09 | Michigan Technological University | Methods of using black bear parathyroid hormone |
WO2008019062A3 (en) * | 2006-08-04 | 2009-04-09 | Gen Hospital Corp | Polypeptide derivatives of parathyroid hormone (pth) |
JP2009545320A (en) * | 2006-08-04 | 2009-12-24 | ザ ジェネラル ホスピタル コーポレイション | Polypeptide derivative of parathyroid hormone (PTH) |
US9057727B2 (en) | 2007-08-01 | 2015-06-16 | The General Hospital Corporation | Screening methods using G-protein coupled receptors and related compositions |
US8987201B2 (en) | 2009-12-07 | 2015-03-24 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
US9492508B2 (en) | 2010-05-13 | 2016-11-15 | The General Hospital Corporation | Parathyroid hormone analogs and uses thereof |
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