WO2000021532A1 - Methods for inhibiting bone resorption - Google Patents
Methods for inhibiting bone resorption Download PDFInfo
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- WO2000021532A1 WO2000021532A1 PCT/US1999/023616 US9923616W WO0021532A1 WO 2000021532 A1 WO2000021532 A1 WO 2000021532A1 US 9923616 W US9923616 W US 9923616W WO 0021532 A1 WO0021532 A1 WO 0021532A1
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/88—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving prostaglandins or their receptors
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- G—PHYSICS
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- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/10—Screening for compounds of potential therapeutic value involving cells
Definitions
- the present invention relates to methods for inhibiting bone resorption in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype antagonist.
- disorders in humans and other mammals involve or are associated with abnormal bone reso ⁇ tion.
- Such disorders include, but are not limited to, osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
- osteoporosis which in its most frequent manifestation occurs in postmenopausal women.
- Osteoporosis is a systemic skeletal disease characterized by a low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Osteoporotic fractures are a major cause of morbidity and mortality in the elderly population. As many as 50% of women and a third of men will experience an osteoporotic fracture. A large segment of the older population already has low bone density and a high risk of fractures. There is a significant need to both prevent and treat osteoporosis and other conditions associated with bone reso ⁇ tion. Because osteoporosis, as well as other disorders associated with bone loss, are generally chronic conditions, it is believed that appropriate therapy will typically require chronic treatment.
- Normal bone physiology involves a process wherein bone tissue is continuously being turned over by the processes of modeling and remodeling. In other words, there is normally an appropriate balance between reso ⁇ tion of existing bone tissue and the formation of new bone tissue. The exact mechanism underlying the coupling between bone reso ⁇ tion and formation is still unknown. However, an imbalance in these processes is manifested in various disease states and conditions of the skeleton.
- osteoblasts Two different types of cells called osteoblasts and osteoclasts are involved in the bone formation and reso ⁇ tion processes, respectively. See H. Fleisch, Bisphosphonates In Bone Disease, From The Laboratory To The Patient, 3rd Edition,
- Osteoblasts are cells that are located on the bone surface. These cells secrete an osseous organic matrix, which then calcifies. Substances such as fluoride, parathyroid hormone, and certain cytokines such as protaglandins are known to provide a stimulatory effect on osetoblast cells.
- an aim of current research is to develop therapeutic agents that will selectively increase or stimulate the bone formation activity of the osteoblasts.
- Osteoclasts are usually large multinucleated cells that are situated either on the surface of the cortical or trabecular bone or within the cortical bone. The osteoclasts resorb bone in a closed, sealed-off microenvironment located between the cell and the bone. The recruitment and activity of osteoclasts is known to be influenced by a series of cytokines and hormones. It is well known that bisphosphonates are selective inhibitors of osteoclastic bone reso ⁇ tion, making these compounds important therapeutic agents in the treatment or prevention of a variety of systemic or localized bone disorders caused by or associated with abnormal bone reso ⁇ tion. However, despite the utility of bisphosphonates there remains the desire amongst researchers to develop additional therapeutic agents for inhibiting the bone reso ⁇ tion activity of osteoclasts.
- Prostaglandins are alicyclic compounds related to the basic compound prostanoic acid.
- a natural prostaglandin, PGE2 has the following structure.
- Prostaglandins such as PGE2 are known to stimulate bone formation and increase bone mass in mammals, including man. It is believed that four different receptor subtypes, designated EP ⁇ , EP2, EP3, and EP4 are involved in mediating the bone modeling and remodeling processes of the osteoblasts and osteoclasts.
- the major prostaglandin receptor in bone is EP4, which is believed to provide its effect by signaling via cyclic AMP.
- the scientific information that is currently known about the prostaglandin mediated bone effect is rather limited, because the exact mechanism of action is not known.
- Prostaglandins and their accosted receptors are more fully described in for example, K.
- antagonists of the EP4 subtype receptor are useful for inhibiting bone reso ⁇ tion. Without being limited by theory, it is believed that these antagonists are responsible for inhibiting the bone reso ⁇ tion activity of the osteoclasts .
- the present invention relates to methods for inhibiting bone reso ⁇ tion in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype antagonist having an EC50 value of from about 0.1 nanoM to about 100 microM.
- the present invention relates to methods for treating or reducing the risk of contracting a disease state or condition involving bone tissue in a mammal in need of such treatment or risk reduction, comprising administering to said mammal a therapeutically effective amount of an EP4 receptor subtype antagonist.
- the present invention relates to methods for inhibiting bone reso ⁇ tion in a mammal in need thereof comprising administering to said mammal a therapeutically effective amount of an EP4 receptor subtype antagonist and a bisphosphonate active.
- the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of an EP4 receptor subtype antagonist.
- the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of an EP4 receptor subtype antagonist and a bisphosphonate active. In further embodiments, the present invention relates to a method for identifying antagonists of an EP4 receptor subtype.
- the present invention relates to the use of a composition in the manufacture of a medicament for inhibiting bone reso ⁇ tion in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype antagonist.
- the present invention relates to methods for inhibiting bone reso ⁇ tion in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype antagonist having an EC50 value of from about 0.1 nanoM to about 100 microM.
- Prostaglandins E (especially PGE2) stimulate bone formation and increase bone mass in several species, including man. The mechanism of this effect, the target cells and the receptors involved are not completely known. Specific cell- surface receptors for PGE2, such as EP j _4, which employ different secondary messenger systems have been cloned and characterized. It is believed that cyclic AMP may have a role in osteogenesis induced by PGE2. The expression of the EP2 and EP4 receptors is found to be involved in cAMP production in the bone tissue of young adult rats (where PGE2 is markedly anabolic), and in various osteoblastic cell lines.
- Osteoblastic cell lines, RCT-1, RCT-3, TRAB-11 and RP-1, as well as osteoblastic cells harvested from fetal rat bones express EP4 mRNA but not EP2 mRNA.
- EP4 mRNA is expressed in tibiae and calvariae of 5-week-old
- PGE2 increases the level of EP4 mRNA which peaks at 2 hours.
- systemic administration of an anabolic dose of PGE2 (3-6 mg/kg) to young adult rats upregulates the expression of EP4 in tibiae and calvariae, an effect which peaks at 1-2 hours.
- anabolic dose of PGE2 3-6 mg/kg
- PGE2 3-6 mg/kg
- the increased expression of EP4 mRNA in the tibial metaphysis following systemic PGE2 treatment is localized to bone marrow cells.
- EP4 is expressed in osteoblastic cells in vitro and in bone marrow putative osteoprogenitor cells in vivo and is upregulated by its ligand, PGE2.
- EP4 is the receptor subtype which mediates the anabolic effects of PGE2.
- Prostaglandins (especially PGE2) have multiple effects on bone, stimulating both reso ⁇ tion and formation.
- Systemic administration of PGE2 or E1 to infants and to animals is clearly anabolic, stimulating bone formation and increases bone mass.
- local administration of PGE2 into long bones stimulates new bone formation, suggesting that that PGE2 acts directly on bone tissue to induce osteogenesis. Histological analysis of bones treated with PGE2 indicates that PGE2 increases the number of osteoblasts present on the bone surface, suggesting that prostaglandins act by recruiting osteoblasts from their precursors.
- PGEs act on various cells via specific cell-surface receptors divided into 4 subtypes, EP. ., according to their relative sensitivity to selective agonists and antagonists.
- the receptor subtypes all belong to the G-protein-coupled receptor family and activate different secondary messenger systems such as adenylate cyclase or phospholipase C.
- EP4 and EP2 activate adenylate cyclase
- EP j activates phospholipase C
- EP3 either lowers intracellular cAMP levels or activates phospholipase C, depending on the specific spliced variant.
- PGE2 stimulates both phosphatidylinositol and cyclic AMP transduction pathways.
- Both EP j and EP4 found in osteoblastic MC3T3-E ] cells are believed to play a role in the biological action of PGE2 in bone tissue.
- PGE1 a potent inducer of bone formation in humans and other species, increases intracellular cyclic AMP but has no effect on phosphatidylinositol turnover in osteoblastic cells.
- EP4 is the major form found in bone tissue, especially in preosteoblasts. See Ikeda T, Miyaura C, Ichikawa A, Narumiya S, Yoshiki S and Suda T, 1995, In situ localization of three subtypes (EP j , EP and EP4) of prostaglandin E receptors in embryonic and newborn mice.
- EP4 but not EP2 is expressed in total RNA from adult rat tibiae and calvariae.
- EP4 is believed to be the major adenylate cyclase-coupled PGE2 receptor expressed in osteoblastic cells and in bone tissue.
- the EP4 receptor subtype is expressed in the bone tissue of young adult rats, in which PGE2 is strongly anabolic.
- EP4 mRNA is expressed in osteoblast precursor cells. It is also found in less differentiated bone cell lines such as RCT-1, TRAB-11 and the RP-1 periosteal cells, but not in fibroblasts. It is highly expressed in bone marrow cells that include osteoblast precursor cells, but not in fully mature osteoblasts on the bone surface. It is believed that PGE2 induces osteogenesis via an increase in the number of active osteoblasts present on the bone surface, resulting from the recruitment of osteoblast precursor cells rather than the enhancement of the activity of existing osteoblasts. It is found that osteoblast precursors are the major target cells for the anabolic effect of PGE2 and that its action in these cells is mediated by EP4 .
- EP4 receptor subtype is believed to be the major receptor which mediates the effects of PGE2 in bone tissue rats. Induction of EP4 by PGE2 further supports its biological role in the bone tissue and points to a mechanism of autoamplification of PGE action.
- the present invention relates to methods for inhibiting bone reso ⁇ tion in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of an EP4 receptor subtype antagonist.
- the methods and compositions of the present invention are useful for both treating and reducing the risk of disease states or conditions associated with abnormal bone reso ⁇ tion.
- disease states or conditions include, but are not limited to, osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid arthritis, periprosthetic osteo lysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma.
- the methods comprise administering a therapeutically effective amount of an EP4 receptor subtype antagonist and a bisphosphonate active.
- an EP4 receptor subtype antagonist and a bisphosphonate active are deemed within the scope of the present invention.
- sequential administration the antagonist and the bisphosphonate can be administered in either order.
- the antagonist and bisphosphonate are typically administered within the same 24 hour period.
- the antagonist and bisphosphonate typically administered within about 4 hours of each other.
- therapeutically effective amount means that amount of the EP4 receptor subtype antagonist, or other actives of the present invention, that will elicit the desired therapeutic effect or response or provide the desired benefit when administered in accordance with the desired treatment regimen.
- a prefered therapeutically effective amount is a bone reso ⁇ tion inhibiting amount.
- “Pharmaceutically acceptable” as used herein means generally suitable for administration to a mammal, including humans, from a toxicity or safety standpoint.
- the agonist is typically administered for a sufficient period of time until the desired therapeutic effect is achieved.
- the term "until the desired therapeutic effect is achieved”, as used herein, means that the therapeutic agent or agents are continuously administered, according to the dosing schedule chosen, up to the time that the clinical or medical effect sought for the disease or condition being mediated is observed by the clinician or researcher.
- the compounds are continuously administered until the desired change in bone mass or structure is observed. In such instances, achieving an increase in bone mass or a replacement of abnormal bone structure with normal bone structure are the desired objectives.
- the compounds are continuously administered for as long as necessary to prevent the undesired condition. In such instances, maintenance of bone mass density is often the objective.
- Nonlimiting examples of administration periods can range from about 2 weeks to the remaining lifespan of the mammal.
- administration periods can range from about 2 weeks to the remaining lifespan of the human, preferably from about 2 weeks to about 20 years, more preferably from about 1 month to about 20 years, more preferably from about 6 months to about 10 years, and most preferably from about 1 year to about 10 years.
- the present invention also relates to methods for identifying compounds useful as antagonists of the EP4 receptor subtype. Compounds so identified are useful for inhibiting bone reso ⁇ tion.
- the present invention relates to a method for identifying compounds which antagonize an EP4 receptor subtype comprising: a). contacting a putative antagonist of an EP4 receptor subtype with a cell culture; and b). determining the antagonist activity of said putative agonist with a cell culture not contacted with said putative antagonist.
- compositions of the present invention comprise a therapeutically effective amount of an EP4 receptor antagonist.
- compositions can further comprise a pharmaceutically- acceptable carrier.
- these compositions also comprise a bisphosphonate active.
- the methods and compositions of the present invention comprise an EP4 receptor subtype antagonist.
- antagonist as used herein, is used in its standard meaning to mean a chemical substance that opposed the physiological effects of another substance.
- an antagonist is a chemical substance that opposes the receptor-associated responses normally induced by another bioactive agent.
- the antagonists useful herein generally have an EC50 va l ue fr° m about
- the antagonists have an EC50 value of from about 0.01 microM to about 10 microM. In a further subclass of the present invention, the antagonists have an EC50 value of from about 0.1 microM to about 10 microM.
- EC50 is a common measure of antagonist activity well known to those of ordinary skill in the art and is defined as the concentration or dose of an antagonist that is needed to produce half, i.e. 50%, of the maximal effect. See also, Goodman and Gilman's, The Pharmacologic Basis of Therapeutics, 9th edition, 1996, chapter 2, E. M. Ross, Pharmacodynamics, Mechanisms of Drug Action and the Relationship Between Drug Concentration and Effect, which is incoroporated by reference herein in its entirety.
- Nonlimiting examples of antagonists useful herein are selected fom the group consisting of
- the antagonists useful herein are compounds that do not contain a cyclopentanone or hydroxycyclopentane ring. In other words, these are non-cyclopentanone and non-hydroxycyclopentane structures.
- the methods and compositions of the present invention can further comprise a bisphosphonate active.
- the bisphosphonates of the present invention correspond to the chemical formula P0 3 H 2
- n is an integer from 0 to 7 and wherein A and X are independently selected from the group consisting of H, OH, halogen, NH2, SH, phenyl, C1-C30 alkyl, C3- C30 branched or cycloalkyl, C1-C30 substituted alkyl, C1-C10 alkyl substituted NH2, C3-C10 branched or cycloalkyl substituted NH2, C1-C10 dialkyl substituted NH2, C3-C10 branched or cycloalkyl disubstituted NH2, C1-C10 alkoxy, C1-C10 alkyl substituted thio, thiophenyl, halophenylthio, C1-C10 alkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl, imidazopyridinyl, and benzyl, such that both A and X are independently
- the alkyl groups can be straight, branched, or cyclic, provided that sufficient atoms are selected for the chemical formula.
- the C1-C30 substituted alkyl can include a wide variety of substituents, nonlimiting examples which include those selected from the group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH2, C1-C10 alkyl or dialkyl substituted NH2, OH, SH, and Cl -CIO alkoxy.
- the foregoing chemical formula is also intended to encompass complex carbocyclic, aromatic and hetero atom structures for the A and/or X substituents, nonlimiting examples of which include naphthyl, quinolyl, isoquinolyl, adamantyl, and chlorophenylthio.
- a non-limiting class of structures useful in the instant invention are those in which A is selected from the group consisting of H, OH, and halogen, X is selected from the group consisting of C1-C30 alkyl, C1-C30 substituted alkyl, halogen, and C1-C10 alkyl or phenyl substituted thio, and n is 0.
- a non-limiting subclass of structures useful in the instant invention are those in which A is selected from the group consisting of H, OH, and Cl, X is selected from the group consisting of C1-C30 alkyl, C1-C30 substituted alkyl, Cl, and chlorophenylthio, and n is 0.
- a non-limiting example of the subclass of structures useful in the instant invention is when A is OH and X is a 3-aminopropyl moiety, and n is 0, so that the resulting compound is a 4-amino-l,-hydroxybutylidene- 1,1 -bisphosphonate, i.e. alendronate.
- Pharmaceutically acceptable salts and derivatives of the bisphosphonates are also useful herein.
- Nonlimiting examples of salts include those selected from the group consisting alkali metal, alkaline metal, ammonium, and mono-, di, tri-, or tetra-Cl-C30-alkyl-substituted ammonium.
- Preferred salts are those selected from the group consisting of sodium, potassium, calcium, magnesium, and ammonium salts.
- Nonlimiting examples of derivatives include those selected from the group consisting of esters, hydrates, and amides.
- bisphosphonate and “bisphosphonates”, as used herein in referring to the therapeutic agents of the present invention are meant to also encompass diphosphonates, biphosphonic acids, and diphosphonic acids, as well as salts and derivatives of these materials.
- the use of a specific nomenclature in referring to the bisphosphonate or bisphosphonates is not meant to limit the scope of the present invention, unless specifically indicated. Because of the mixed nomenclature currently in use by those or ordinary skill in the art, reference to a specific weight or percentage of a bisphosphonate compound in the present invention is on an acid active weight basis, unless indicated otherwise herein.
- the phrase "about 5 mg of a bisphosphonate selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof, on an alendronic acid active weight basis” means that the amount of the bisphosphonate compound selected is calculated based on 5 mg of alendronic acid. For other bisphosphonates, the amount of bisphosphonate is calculated based on the corresponding bisphosphonic acid.
- Nonlimiting examples of bisphosphonates useful herein include the following:
- Alendronate also known as alendronate sodium or alendronate monosodium trihydrate
- 4-amino-l-hydroxybutylidene- 1,1 -bisphosphonic acid monosodium trihydrate 4-amino-l-hydroxybutylidene- 1,1 -bisphosphonic acid monosodium trihydrate.
- 1,1-dichloromethylene- 1,1 -diphosphonic acid (clodronic acid), and the disodium salt (clodronate, Procter and Gamble), are described in Belgium Patent 672,205 (1966) and J. Org. Chem 32, 4111 (1967), both of which are inco ⁇ orated by reference herein in their entirety.
- (zolendronate) A non-limiting class of bisphosphonates useful in the instant invention are selected from the group consisting of alendronate, cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, pharmaceutically acceptable salts thereof, and mixtures thereof.
- a non- limiting subclass of the above-mentioned class in the instant case is selected from the group consisting of alendronate, pharmaceutically acceptable salts thereof, and mixtures thereof.
- a non-limiting example of the subclass is alendronate monosodium trihydrate.
- the EP4 receptor subtype antagonists, and in further embodiments the bisphosphonate actives and any other additional actives are typically administered in admixture with suitable pharmaceutically acceptable diluents, excipients, or carriers, collectively referred to herein as "carrier materials", suitably selected with respect to the mode of administration.
- suitable pharmaceutically acceptable diluents, excipients, or carriers collectively referred to herein as "carrier materials”, suitably selected with respect to the mode of administration.
- suitable pharmaceutically acceptable diluents, excipients, or carriers collectively referred to herein as "carrier materials”
- suitable pharmaceutically acceptable diluents, excipients, or carriers collectively referred to herein as "carrier materials”
- suitable pharmaceutically acceptable diluents, excipients, or carriers collectively referred to herein as "carrier materials”
- suitable pharmaceutically acceptable diluents, excipients, or carriers collectively referred to herein as "carrier materials
- the active ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like.
- an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, croscarmellose sodium and the like.
- the oral drug components can be combined with any oral, non- toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- suitable binders, lubricants, disintegrating agents and coloring agents can also be inco ⁇ orated.
- Suitable binders can include starch, gelatin, natural sugars such a glucose, anhydrous lactose, free-flow lactose, beta-lactose, and corn sweeteners, natural and synthetic gums, such as acacia, guar, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes, and the like.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- An example of a tablet formulation is that described in U.S. Patent No.
- the compounds used in the present method can also be coupled with soluble polymers as targetable drug carriers.
- soluble polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropyl- methacrylamide, and the like.
- 5-week old Sprague-Dawley rats (Charles River) are euthanized by CO2, their tibiae and calvariae are excised, cleaned of soft tissues and frozen immediately in liquid nitrogen.
- 6-week old rats are given a single injection of either vehicle (7% ethanol in sterile water) or an anabolic dose of PGE2 (Cayman Chemical, Ann Arbor, MI), 3-
- Animals are euthenized at several time points post-injection and their tibiae and calvariae, as well as samples from lung and kidney tissues are frozen in liquid nitrogen.
- RP-1 periosteal cells are spontaneously immortalized from primary cultures of periosteal cells from tibae of 4-week old Sprague-Dawley rats and are cultured in DMEM (BRL, Gaithersburg, MD) with 10 % fetal bovine serum (JRH Biosciences, Lenexa, KS). These cells do not express osteoblastic phenotypic markers in early culture, but upon confluence, express type I collagen, alkaline phosphatase and osteocalcin and produce mineralized extracellular matrix.
- RCT-1 and RCT-3 are clonal cell lines immortalized by SV-40 large T antigen from cells released from fetal rat calvair by a cmbination collagenase/hyaluronidase digestion.
- RCT-1 cells derived from cells released during the first 10 minutes of digestion (fraction I), are cultured in RPMI 1640 medium (BRL) with 10% fetal bovine serum and 0.4 mg/ml G418 (BRL). These cells differentiate and express osteoblastic features upon retinoic acid treatment.
- RCT-3 cells immortalized from osteoblast-enriched fraction HI cells, are cultured in F-12 medium (BRL) with 5% Fetal bovine serum and 0.4 mg/ml G418.
- TRAB-11 cells are also immortalized by SV40 large T antigen from adult rat tibia and are cultured in
- fraction IIT primary fetal rat calvaria cells are obtained by collagenase/hyaluronidase digestion of calvariae of 19 day-old rat fetuses. See Rodan et al., Growth stimulation of rat calvaria osteoblastic cells by acidic FGF, Endocrinology, 121, 1919-1923
- FBS normal rat kidney fibroblasts
- NRK normal rat kidney fibroblasts
- RNA is extracted from the tibial metaphysis or diaphysis and calvaria using a guanidinium isothiocyanate-phenol-chloroform method after pulverizing frozen bone samples by a tissue homogenizer. See P. Chomczynski et al., Single-step method of RNA isolation by acid guanidium thiocyanate-phenol- chloroform extraction., Analyt Biochem, 162, 156-159 (1987), which is inco ⁇ orated by reference herein in its entirety. RNA samples (20 mg) are separated on 0.9% agarose/formaldehyde gels and transferred onto nylon membranes (Boehringer Mannheim, Germany).
- Membranes are prehybridized in Hybrisol I (Oncor, Gaithersburg, MD) and 0.5 mg/ml sonicated salmon sperm DNA (Boehringer) at 42°C for 3 hours and are hybridized at 42°C with rat EP2 and mouse EP4 cDNA probes labeled with [32p]-dCTP (Amersham, Buckinghamshire, UK) by random priming using the rediprime kit (Amersham). After hybridization, membranes are washed 4 times in 2xSSC + 0.1% SDS at room temperature for a total of 1 hour and once with 0.2xSSC + 0.1% SDS at 55°C for 1 hour and then exposed to Kodak XAR 2 film at -70°C using intensifying screens.
- bound probes are removed twice with 0.1% SDS at 80°C and membranes are hybridized with a human GAPDH (Glyceraldehyde 3-Phosphate Dehydrogenase) cDNA probe (purchased from Clontech, Palo Alto, CA) for loading control.
- GAPDH Glyceraldehyde 3-Phosphate Dehydrogenase
- Frozen tibiae are sectioned coronally at 7 mm thickness and sections are mounted on charged slides (Probe On Plus, Fisher Scientific, Springfield, NJ) and are kept at -70°C until hybridization.
- cRNA probes are labeled with 35 S-UTPgS (ICN, Costa Mesa, CA) using a Riboprobe II kit (Promega Madison, WI).
- Hybridization is performed overnight at 50° C. See M. Weinreb et al, Different pattern of alkaline phosphatase, osteopontin and osteocalcin expression in developing rat bone visualized by in-situ hybridization, J. Bone Miner Res., 5, 831-842 (1990) and D. Shinar et al., Expression ofalphav and beta3 integrin subunits in rat osteoclasts in situ, J. Bone Miner. Res., 8, 403-414 (1993), which are both inco ⁇ orated by reference herein in their entirety.
- EP4 and EP2 mRNA are examined in various bone derived cells including osteoblast-enriched primary rat calvaria cells, immortalized osteoblastic cell lines from fetal rat calvaria or from adult rat tibia and an osteoblastic osteosarcoma cell line. Most of the osteoblastic cells and cell lines show significant amounts of 3.8 kb EP4 mRNA, except for the rat osteosarcoma cell line ROS 17/2.8. Consistent with this finding, in ROS 17/2.8 cells PGE2 has no effect on intracellular cAMP, which is markedly induced in RCT-3 and TRAB-11 cells. Treatment of RCT-1 cells with retinoic acid, which promotes their differentiation, reduces the levels of EP4 mRNA.
- NRK fibroblasts do not express EP4 mRNA, while P815 mastocytoma cells, used as positive controls, express large amounts of EP4 mRNA. In contrast to EP4 mRNA, none of the osteoblastic cells and cell lines express detectable amounts of EP2 mRA in total RNA samples. Expression of EP4 mRNA in osteoblastic cells, EP4 is also expressed in total RNA isolated from tibiae and calvariae of 5-week-old rats. In contrast, no EP2 mRNA is found in RNA from tibial shafts.
- PGE2 enhances its own production via upregulation of cyclooxygenase 2 expression in osteoblasts and in bone tissue thus autoamplifying its own effects.
- RP-1 cells are immortalized from a primary culture of adult rat tibia periosteum is examined. These cells express osteoblast phenotypic makers upon confluence and form mineralized bone matrix when implanted in nude mice. Similar to the other osteoblastic cells examined, RP-1
- periosteal cells express a 3.8 kb EP4 transc ⁇ pt.
- Treatment with PGE2 (10- M) rapidly increases EP4 mRNA levels peaking at 2 hours after treatment.
- PGE2 has no effect on EP4 mRNA levels in the more differentiated RCT-3 cells.
- EP2 mRNA is not expressed in RP-1 cells before or after treatment with PGE2.
- week-old male rats are injected with PGE2 (3 - 6 mg/Kg). Systemic administration of PGE2 rapidly increased EP4 mRNA levels in the tibialt diaphysis peaking at 2 h after injection.
- PGE2 A similar effect of PGE2 on EP4 mRNA is observed in the tibial metaphysis and in calvaria.
- PGE2 induces EP4 mRNA levels in vitro in osteogenic periosteal cells and in vivo in bone tissue in a cell-specific and tissue- specific manner.
- PGE2 does not include EP2 mRNA in RP-1 cells nor in bone tissue.
- EP4 is expressed in osteoblastic cells in vitro and in bone marrow cells in vivo and is upregulated by its ligand, PGE2.
- Pharmaceutical tablets are prepared using standard mixing and formation techniques. Tablets containing about 1 to 100 mg of an EP4 receptor subtype antagonist are prepared using the following relative weights of ingredients.
- the resulting tablets are useful for administration in accordance with the methods of the present invention for inhibiting bone reso ⁇ tion.
- tablets are prepared that also contain 5 or 10 mg of a bisphosphonate active, on a bisphosphonic acid active basis, of a bisphosphonate selected from the group consisting of alendronate cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts thereof.
- a bisphosphonate active on a bisphosphonic acid active basis, of a bisphosphonate selected from the group consisting of alendronate cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts thereof.
- Liquid formulations are prepared using standard mixing techniques.
- a liquid formulation containing about 1 to about 100 mg of an EP4 receptor subtype antagonist is prepared using the following relative weights of ingredients.
- the resulting liquid formulation is useful for administration for inhibiting bone reso ⁇ tion.
- solutions are prepared also containing 5 or 10 mg of a bisphosphonate active, on a bisphosphonic acid active basis, of a bisphosphonate selected from the group consisting of alendronate cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts thereof.
- a bisphosphonate active on a bisphosphonic acid active basis, of a bisphosphonate selected from the group consisting of alendronate cimadronate, clodronate, tiludronate, etidronate, ibandronate, neridronate, olpandronate, risedronate, piridronate, pamidronate, zolendronate, and pharmaceutically acceptable salts thereof.
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Abstract
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Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002346038A CA2346038A1 (en) | 1998-10-15 | 1999-10-12 | Methods for inhibiting bone resorption |
EP99970321A EP1148877A4 (en) | 1998-10-15 | 1999-10-12 | Methods for inhibiting bone resorption |
AU14442/00A AU1444200A (en) | 1998-10-15 | 1999-10-12 | Methods for inhibiting bone resorption |
JP2000575508A JP2002527393A (en) | 1998-10-15 | 1999-10-12 | Bone resorption inhibition method |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10433998P | 1998-10-15 | 1998-10-15 | |
US60/104,339 | 1998-10-15 | ||
GB9824572.3 | 1998-11-09 | ||
GBGB9824572.3A GB9824572D0 (en) | 1998-11-09 | 1998-11-09 | Methods for inhibiting bone resorption |
Publications (1)
Publication Number | Publication Date |
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WO2000021532A1 true WO2000021532A1 (en) | 2000-04-20 |
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ID=26314644
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1999/023616 WO2000021532A1 (en) | 1998-10-15 | 1999-10-12 | Methods for inhibiting bone resorption |
Country Status (5)
Country | Link |
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EP (1) | EP1148877A4 (en) |
JP (1) | JP2002527393A (en) |
AU (1) | AU1444200A (en) |
CA (1) | CA2346038A1 (en) |
WO (1) | WO2000021532A1 (en) |
Cited By (17)
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EP1110949A1 (en) * | 1999-12-22 | 2001-06-27 | Pfizer Products Inc. | EP4 receptor selective agonists in the treatment of osteoporosis |
WO2002032422A2 (en) * | 2000-10-19 | 2002-04-25 | Pfizer Pharmaceuticals Inc. | Ep4 receptor inhibitors to treat rheumatoid arthritis |
WO2002050031A1 (en) * | 2000-12-21 | 2002-06-27 | Glaxo Group Limited | Indole derivatives |
WO2003030911A1 (en) * | 2001-10-08 | 2003-04-17 | Medical Research Council | Use of prostaglandin e synthase inhibitors, or ep2 or ep4 receptor antagonists, in the treatment of a pathological condition of the uterus |
US6747054B2 (en) | 2000-11-27 | 2004-06-08 | Pfizer Inc. | EP4 receptor selective agonists in the treatment of osteoporosis |
US6849657B2 (en) | 2001-07-16 | 2005-02-01 | Syntex (U.S.A.) Llc | 2-pyrrolidone derivatives as prostanoid agonists |
US6900336B2 (en) | 2001-07-16 | 2005-05-31 | Syntex (U.S.A.) Llc | 8-aza-11-deoxy prostaglandin analogues |
US7166631B2 (en) | 2001-02-09 | 2007-01-23 | Glaxo Group Limited | Benzo[f]isoindole derivatives with affinity to the EP4 receptor |
US7179820B2 (en) | 2003-06-06 | 2007-02-20 | Allergan, Inc. | Piperidinyl prostaglandin E analogs |
WO2007088190A1 (en) | 2006-02-03 | 2007-08-09 | Glaxo Group Limited | Benzo (f) isoindol-2-ylphenyl acetic acid derivatives as ep4 receptor agonists |
US7271183B2 (en) | 2003-01-10 | 2007-09-18 | Roche Palo Alto Llc | 2-Piperidone derivatives as prostaglandin agonists |
WO2008071736A1 (en) | 2006-12-15 | 2008-06-19 | Glaxo Group Limited | Benzamide derivatives as ep4 receptor agonists |
WO2009056582A1 (en) | 2007-11-02 | 2009-05-07 | Glaxo Group Limited | Novel compounds |
US7608637B2 (en) | 2001-07-23 | 2009-10-27 | Ono Pharmaceutical Co., Ltd. | Pharmaceutical composition for treatment of diseases associated with decrease in bone mass comprising EP4 agonist as the active ingredient |
WO2010087425A1 (en) | 2009-01-30 | 2010-08-05 | 国立大学法人京都大学 | Prostate cancer progression inhibitor and progression inhibition method |
US8513027B2 (en) | 1997-09-25 | 2013-08-20 | Asterand Uk Acquisition Limited | Method of identifying an inhibitor of the prostanoid EP4 receptor |
WO2013167582A1 (en) | 2012-05-09 | 2013-11-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and pharmaceutical compositions for prevention or treatment of chronic obstructive pulmonary disease |
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US5411980A (en) * | 1989-07-28 | 1995-05-02 | Merck & Co., Inc. | Substituted triazolinones, triazolinethiones, and triazolinimines as angiotensin II antagonists |
Family Cites Families (1)
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WO1993001177A1 (en) * | 1991-07-03 | 1993-01-21 | Merck & Co., Inc. | Substituted triazolinones |
-
1999
- 1999-10-12 WO PCT/US1999/023616 patent/WO2000021532A1/en not_active Application Discontinuation
- 1999-10-12 JP JP2000575508A patent/JP2002527393A/en not_active Withdrawn
- 1999-10-12 CA CA002346038A patent/CA2346038A1/en not_active Abandoned
- 1999-10-12 EP EP99970321A patent/EP1148877A4/en not_active Withdrawn
- 1999-10-12 AU AU14442/00A patent/AU1444200A/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US5411980A (en) * | 1989-07-28 | 1995-05-02 | Merck & Co., Inc. | Substituted triazolinones, triazolinethiones, and triazolinimines as angiotensin II antagonists |
Non-Patent Citations (6)
Title |
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DATABASE CAPLUS ON STN (COLUMBUS, OHIO, USA); ASHTON W.: "Substituted triazolinones, triazolinethiones and triazolinimines as angiotensin II antagonists" * |
DATABASE HCAPLUS ON STN (COLUMBUS, OHIO, USA); SATO M.: "Effects of bisphosphonates on isolated rat osteoclasts as examined by reflected light microscopy" * |
DATABASE MEDLINE ON STN (COLUMBUS, OHIO, USA); NISHGAKI N.: "Identification of prostaglandin E receptor 'EP2' cloned from mastocytoma cells Ep4 subtype" * |
FEBS LETTERS, 15 May 1995 (1995-05-15) * |
J. BONE MINER. RES., 1990 * |
See also references of EP1148877A4 * |
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Also Published As
Publication number | Publication date |
---|---|
EP1148877A4 (en) | 2003-01-22 |
JP2002527393A (en) | 2002-08-27 |
CA2346038A1 (en) | 2000-04-20 |
AU1444200A (en) | 2000-05-01 |
EP1148877A1 (en) | 2001-10-31 |
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