EP1200076A4 - CALCILYTIC COMPOUNDS - Google Patents

CALCILYTIC COMPOUNDS

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Publication number
EP1200076A4
EP1200076A4 EP00952319A EP00952319A EP1200076A4 EP 1200076 A4 EP1200076 A4 EP 1200076A4 EP 00952319 A EP00952319 A EP 00952319A EP 00952319 A EP00952319 A EP 00952319A EP 1200076 A4 EP1200076 A4 EP 1200076A4
Authority
EP
European Patent Office
Prior art keywords
dimethyl
hydroxy
phenoxy
propyl
cyano
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.)
Withdrawn
Application number
EP00952319A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP1200076A1 (en
Inventor
Maxine Gowen
Larry J Suva
John Fox
George B Stroup
Edward F Nemeth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shire NPS Pharmaceuticals Inc
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
NPS Pharmaceuticals Inc
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Filing date
Publication date
Application filed by SmithKline Beecham Corp, NPS Pharmaceuticals Inc filed Critical SmithKline Beecham Corp
Publication of EP1200076A1 publication Critical patent/EP1200076A1/en
Publication of EP1200076A4 publication Critical patent/EP1200076A4/en
Withdrawn legal-status Critical Current

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/12Drugs for disorders of the metabolism for electrolyte homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/12Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/18Drugs for disorders of the endocrine system of the parathyroid hormones

Definitions

  • the present invention relates to the treatment of a variety of diseases associated with abnormal bone or mineral homeostasis, including but not limited to hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease and osteoporosis.
  • the present methods involve the co-administration of an orally active antagonist of the calcium receptor with an anti-resorptive agent.
  • extracellular Ca ⁇ + is under tight homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and cellular function.
  • Extracellular Ca ⁇ + inhibits the secretion of parathyroid hormone ("PTH") from parathyroid cells, inhibits bone resorption by osteoclasts, and stimulates secretion of calcitonin from thyroid C-cells.
  • PTH parathyroid hormone
  • Calcium receptor proteins enable certain specialized cells to respond quickly to changes in extracellular Ca- + concentration.
  • PTH is the principal endocrine factor regulating Ca ⁇ + homeostasis in the blood and extracellular fluids. PTH, by acting on bone and kidney cells, increases the level of Ca2+ in the blood. This increase in extracellular Ca ⁇ + acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between extracellular Ca ⁇ + and PTH secretion forms an important mechanism maintaining bodily Ca2+ homeostasis.
  • Extracellular Ca2+ acts directly on parathyroid cells to regulate PTH secretion.
  • the existence of a parathyroid cell surface protein which detects changes in extracellular Ca2+ has been confirmed. See Brown et al., Nature 366:574, 1993.
  • this protein the calcium receptor, acts as a receptor for extracellular Ca ⁇ , detects changes in the ion concentration of extracellular Ca ⁇ , and initiates a functional cellular response, PTH secretion.
  • extracellular Ca ⁇ plays a role in parafollicular (C-cells) and parathyroid cells.
  • C-cells parafollicular
  • parathyroid cells See Nemeth, Cell Calcium 11:323, 1990.
  • the role of extracellular Ca ⁇ + on osteoclasts has also been studied. See Zaidi, Bioscience Reports 10:493, 1990.
  • Calcilytics are compounds able to antagonize calcium receptor activity, thereby causing a decrease in one or more calcium receptor activities evoked by extracellular Ca2+.
  • Calcilytics are useful as lead molecules in the discovery, development, design, modification and/or construction of calcium receptor modulators which are active at Ca2+ receptors.
  • Such calcilytics are useful in the treatment of various disease states characterized by abnormal levels of one or more components, e.g., polypeptides such as hormones, enzymes or growth factors, the expression and/or secretion of which is regulated or affected by activity at one or more Ca ⁇ + receptors.
  • Target diseases or disorders for calcilytic compounds include diseases involving abnormal bone and mineral metabolisim.
  • Abnormal calcium homeostasis is characterized by one or more of the following activities: an abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary excretion of calcium; an abnormal increase or decrease in bone calcium levels (for example, as assessed by bone mineral density measurements); an abnormal absorption of dietary calcium; an abnormal increase or decrease in the production and/or release of messengers which affect serum calcium levels such as PTH and calcitonin; and an abnormal change in the response elicited by messengers which affect serum calcium levels.
  • calcium receptor antagonists offer a unique approach towards the pharmacotherapy of diseases associated with abnormal bone or mineral homeostasis, such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease and osteoporosis.
  • the present invention provides novel methods of treatment of a variety of diseases associated with abnormal bone or mineral homeostasis, including but not limited to hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease and osteoporosis.
  • the present methods involve the co-administration of a calcilytic agent with an anti-resorptive agent to a patient in need of treatment.
  • the present calcilytic agents include agents which may cause prolonged PTH elevation.
  • the present agents cause a transient elevation of PTH.
  • Figure 2 represents plasma PTH levels in osteopenic rats treated with calcilytic or rat PTH according to Study 1. Timed plasma samples were collected relative to administration of the agent as indicated, following treatment with calcilytic adminstered (filled circle) or PTH (open circle).
  • Figure 3 represents circulating levels of calcilytic following administration of calcilytic according to Study 1.
  • Figure 4 represents dynamic histomorphometry on proximal tibiae from osteopenic rats following treatment with calcilytic or PTH according to Study 1.
  • Figure 4a represents % labeled perimeter (%L.Pm.)
  • Figure 4b represents % eroded surface (% Er.P)
  • Figure 4c) represents % osteoid perimeter (%Os.Pm)
  • Figure 4d) represents bone formation rate: bone area referent (BFR/B.Ar) %/year
  • Figure 5 represents sections of tibiae stained with Von Kossa from osteopenic ovx rats treated with estrogen +/- calcilytic according to Study 2. Representative sections are shown from animals treated for the next 5 weeks with: Figure 5a) represents vehicle
  • Figure 5b represents 17 ⁇ estradiol (s.c. pellet 0.01 mg/90 days)
  • Figure 5c) represents NPS 2143 (100 umol/kg daily p.o.)
  • Figure 6 represents histomorphometry on proximal tibiae from osteopenic rats following treatment with calcilytic plus/minus 17 ⁇ estradiol according to Study 2.
  • Figure 6a represents % trabecular bone area (%Tb.Ar)
  • Figure 6b represents bone formation rate: tissue area referent (BFR/T.Ar) %/year
  • calcilytic compounds of the present invention include all calcilytic compounds.
  • calcilytic compound it is meant that the compound is able to inhibit calcium receptor activity, thereby causing a decrease in one or more calcium receptor activities evoked by extracellular Ca2+.
  • Such compounds include, but are not limited to a compound selected from the group consisting of:
  • Bone is composed of a protein matrix in which spindle- or plate-shaped crystals of hydroxyapatite are incorporated.
  • Type I Collagen represents the major structural protein of bone comprising approximately 90% of the structural protein. The remaining 10% of matrix is composed of a number of non-collagenous proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein.
  • Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
  • Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage.
  • the osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (i.e., resorbing) surface.
  • the low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix. In this way, a resorption lacuna, or pit, is formed.
  • osteoblasts lay down a new protein matrix that is subsequently mineralized.
  • disease states such as osteoporosis and Paget's disease
  • the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle.
  • this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
  • anti-resorptive means an agent capable of preventing, delaying or retarding bone resorption.
  • Anti resorptive agents useful in the present invention include, but are not limited to, estrogen, 1, 25 (OH)2 vitamin D3, calcitonin, bisphosphonate and cathepsin K inhibitors.
  • the present compounds can also be formulated as pharmaceutically acceptable salts and complexes thereof.
  • Pharmaceutically acceptable salts are non- toxic salts in the amounts and concentrations at which they are administered.
  • Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, cyclohexylsulfamate and quinate.
  • Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
  • Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present.
  • a compound of the present invention or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the calcilytic compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or transmucosal administration.
  • oral administration is preferred.
  • the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.
  • injection parenteral administration
  • the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution.
  • the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.
  • detergents may be used to facilitate permeation.
  • Transmucosal administration may be through nasal sprays, rectal suppositories, or vaginal suppositories.
  • the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.
  • the amounts of various calcilytic compounds to be administered can be determined by standard procedures taking into account factors such as the compound
  • IC50 the biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.
  • Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered.
  • the composition is in unit dosage form.
  • a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered.
  • dosing is such that the patient may administer a single dose.
  • Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/Kg, and preferably from 0.1 to 50 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, calculated as the free base.
  • the daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/Kg, of a compound of Formula(I).
  • a topical formulation contains suitably 0.01 to 5.o% of a compound of Formula (I).
  • the active ingredient may be administered from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.
  • treatment of a disease includes, but is not limited to prevention, retardation and prophylaxis of the disease.
  • Diseases and disorders which might be treated or prevented, based upon the affected cells include bone and mineral-related diseases or disorders; hypoparathyroidism; those of the central nervous system such as seizures, stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage, such as occurs in cardiac arrest or neonatal distress, epilepsy, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease, dementia, muscle tension, depression, anxiety, panic disorder, obsessive-compulsive disorder, post- traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, and Tourette 's syndrome; diseases involving excess water reabso ⁇ tion by the kidney, such as syndrome of inappropriate ADH secretion (SIADH), cirrhosis, congestive heart failure, and nephrosis; hypertension; preventing and/or decreasing renal toxicity from cationic antibiotics (e.g., aminoglycoside antibiotics); gut motility disorders such as diarrhea and spastic colon; GI ulcer diseases; GI diseases with excessive calcium abs
  • the present compounds are used to increase serum parathyroid ("PTH") levels in a non-pulsatile manner.
  • PTH serum parathyroid
  • Increasing serum PTH levels may be helpful in treating diseases such as hypoparathyroidism, osteosarcoma,, periodontal disease, fracture, osteoarthritis, rheumatoid arthritis, Paget's disease and osteoporosis.
  • abnormally low serum PTH means a serum PTH level lower than that occurring in the general population, and is preferably an amount associated with a disease or onset of a disease.
  • Increasing serum PTH levels can be used to treat various diseases including bone and mineral related diseases.
  • the duration of PTH level increase is 12 hours or longer, more preferably 18 hours or longer and most preferably 24 hours or longer.
  • the increase in PTH is 3 fold or lower than the normal range for intact PTH in humans. More preferably, the increase in PTH level is 2-fold or lower than the normal range.
  • compositions comprising the present compounds and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
  • compositions are in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are inco ⁇ orated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of the present invention or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
  • Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose. No unacceptable toxological effects are expected when compounds of the present invention are administered in accordance with the present invention.
  • BMD was determined by DXA (QDR-4500 Hologic, Waltham, Mass) prior to treatment and at weeks 4 and 8. At term tibiae were removed for histological analysis. All animals received tetracycline 10 and 3 days prior to the start of dosing and calcein (10 mg/kg) 10 and 3 days prior to sacrifice. Study 2 Animals were prepared and monitored as described above.
  • Groups consisted of sham and ovx controls which were treated with oral dose vehicle (20% aqueous encapsin), and 4 additional ovx groups that received either N-[(2R-Hydroxy-3-[(3- chloro-2-cyano)phenoxy-propyl]- 1 , 1 -dimethyl-2-(2-naphthyl)ethyl amine hydrochloride(100 umol/kg/d, p.o.), 17 ⁇ estradiol (s.c.
  • Measurements within the tibial metaphysis were restricted to a mean tissue area of approximately 8 mm beginning 1 mm below the growth plate.
  • Primary measurements included area of bone and marrow (mm ), bone area (mm ), perimeter of bone (mm), single and double-labelled perimeter (sL.Pm, dL.Pm, mm), osteoid perimeter (O.Pm, mm) and eroded perimeter (Er.P, mm).
  • Derived indices included trabecular bone volume (%Tb.Ar), trabecular number (Tb.N, mm "1 ), trabecular thickness (Tb.Th, ⁇ m), trabecular separation (Tb.Sp, ⁇ m), bone formation rate, surface referent (BFR/Tb.Pm, ⁇ m 3 / ⁇ m 2 /year), BFR/Tb.Ar (bone area referent, %/year), BFR/B.Ar (tissue referent, %/year) and mineral apposition rate (MAR, ⁇ m day), and percent labelled perimeter (%Lp).
  • Statistical analysis was assessed by a two sided t-test.
  • the assay was performed essentially as in Votta, Bone, Vol. 15, pp. 533-538, (1994).
  • Timed-pregnant Sprague-Dawley rats (Taconic Farms, Germantown, NY) were injected subcutaneously with 200 microcuries of 45rj a Q2 on day 18 of gestation, housed overnight, then anesthetized with Innovar-Vet (Pittman-Moore, Mundelein, IL) and sacrificed by cervical dislocation.
  • the fetuses were removed aseptically and the radii and ulnae were dissected free of surrounding soft tissue and cartilagenous ends.
  • ⁇ C ⁇ released into the medium and the residual 45ca in the bones were quantitated by liquid scintillation spectrometry. Data are expressed as the percent 45ca released from treated bones as compared with corresponding control bones. Statistical differences were assessed by a one way analysis of variance (ANOVA). IC-50 values were based on data from two independent experiments. Osteoblast cAMP production and alkaline phosphatase activity cAMP accumulation was measured in both human TF274 osteoblastic cells
  • Bone mineral density was measured in vivo in the lumbar spine, distal femur and proximal tibia immediately before treatment and following eight weeks of dosing. Animals which had been ovariectomized three months previously had lost significant bone mass at all three skeletal sites: 15% at lumbar spine and proximal tibia, 24% at the distal femur.
  • bone mass was unaffected by treatment with N-[(2R-Hydroxy-3-[(3-chloro-2-cyano)phenoxy- propyl]-l,l-dimethyl-2-(2-naphthyl)ethyl amine, but was returned to pre-ovx levels after eight weeks of treatment with 5ug/kg daily PTH in the proximal tibia ( Figure 1).
  • PTH levels in animals given 5 ug/kg PTH were in the same range as those dosed with N-[(2R-Hydroxy-3- [(3-chloro-2-cyano)phenoxy-propyl]- 1 , 1 -dimethyl-2-(2- naphthyl)ethyl amine, but were returned to baseline by 2-4 hours after dosing ( Figure 2).
  • the differences in the duration of the PTH response can be explained by sustained exposure to N-[(2R-Hydroxy-3-[(3-chloro-2-cyano)phenoxy-propyl]-l,l- dimethyl-2-(2-naphthyl)ethyl amine, which was found to be elevated for up to eight hours (Figure 3).
  • Figure 5 shows representative sections of tibiae stained with Von Kossa from animals with no treatment following ovx (5 a), treated with estrogen alone (5b) or treated with estrogen plus N-[(2R-Hydroxy-3-[(3-chloro-2-cyano)phenoxy-propyl]- 1 , 1 -dimethyl- 2-(2-naphthyl)ethyl amine(5c). It is clear that co-administration of N-[(2R- Hydroxy-3-[(3-chloro-2-cyano)phenoxy-propyl]-l,l-dimethyl-2-(2-naphthyl)ethyl amine and estrogen (5c) caused increased bone mass over and above estrogen alone.
  • N-[(2R-Hydroxy-3-[(3-chloro-2- cyano)phenoxy-propyl]-l,l-dimethyl-2-(2-naphthyl)ethyl amine plus estrogen resulted in a two-fold increase in % Tb.Ar. over the ovx group ( Figure 6a). This appears to be due to an increase in trabecular thickness induced by N-[(2R-Hydroxy- 3-[(3-chloro-2-cyano)phenoxy-propyl]-l,l-dimethyl-2-(2-naphthyl)ethyl amine plus estrogen (Table 1).
  • the bone formation rate/tissue area was significantly elevated in the N-[(2R-Hydroxy-3-[(3-chloro-2-cyano)phenoxy-propyl]-l,l-dimethyl-2-(2- naphthyl)ethyl amine plus estrogen group (Figure 6b). Elevation of bone formation rate/tissue area shows that bone mass is increasing in the area measured and reflects new bone formation on bone surfaces that are not being remodeled (modeling), a classic feature of PTH action.
  • N-[(2R-Hydroxy-3-[(3-chloro-2-cyano)phenoxy-propyl]- 1 , 1 -dimethyl-2-(2- naphthyl)ethyl amine had no effect on human osteoclast mediated bone reso ⁇ tion at concentrations up to 3 uM, while an inhibitor of cathepsin K, 3,11-bis (2- methylpropyl)-4,7,10-trioxo-2,5,6,8,9,12-hexaazatridecanedioate inhibited with an IC50 of 0.9 uM.
  • This assay is limited by its sensitivity to DMSO, so concentrations of N-[(2R-Hydroxy-3-[(3-chloro-2-cyano)phenoxy-propyl]-l,l-dimethyl-2-(2- naphthyl)ethyl amine above 3 uM could not be tested.
  • N-[(2R-Hydroxy-3-[(3-chloro-2-cyano)phenoxy-propyl]-l,l-dimethyl-2-(2- naphthyl)ethyl amine inhibited reso ⁇ tion with an IC50 of 11.3 +/- 3 uM.
  • the present data demonstrate that, with regard to the amount of PTH secreted in response N-[(2R-Hydroxy-3-[(3-chloro-2-cyano)phenoxy-propyl]-l,l- dimethyl-2-(2-naphthyl)ethyl amine, a low duration and low fold increase in PTH levels had profound effects on bone turnover.
  • Most published studies on effects of PTH in rats have used a dose of 80 ug/kg. This dose leads to a circulating level of approximately 5,000 - 14,000 pg/ml, compared to the 150-200 pg/ml in our studies. This demonstrates that very low doses of PTH effectively modulate bone turnover.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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AR030684A1 (es) * 2000-01-24 2003-09-03 Smithkline Beecham Corp Compuestos calciliticos, uso de dichos compuestos en la manufactura de medicamentos, e intermediarios utiles en la preparacion de dichos compuestos
US20030018203A1 (en) 2002-07-17 2003-01-23 Largo Maria Amparo Calcilytic compounds
US6756480B2 (en) 2000-04-27 2004-06-29 Amgen Inc. Modulators of receptors for parathyroid hormone and parathyroid hormone-related protein
UY28089A1 (es) 2002-11-26 2004-06-30 Smithkline Beecham Corp Compuestos calciliticos
US7205322B2 (en) 2003-02-12 2007-04-17 Bristol-Myers Squibb Company Thiazolidine compounds as calcium sensing receptor modulators
US7265145B2 (en) 2003-05-28 2007-09-04 Bristol-Myers Squibb Company Substituted piperidines and pyrrolidines as calcium sensing receptor modulators and method
TW200845956A (en) 2006-12-18 2008-12-01 Smithkline Beecham Corp Calcilytic compounds
WO2013098588A1 (en) * 2011-12-27 2013-07-04 Ubaldo Armato Use of calcilytic drugs as a pharmacological approach to the treatment and prevention of alzheimer's disease, alzheimer's disease-related disorders, and down's syndrome neuropathies
GB201217330D0 (en) 2012-09-28 2012-11-14 Univ Cardiff Therapeutic for treating inflammatory lung disorders
CN108420814A (zh) * 2017-02-15 2018-08-21 四川大学 一种nps-2143用于抗菌的新用途
CN116173187B (zh) * 2023-03-14 2024-05-10 哈尔滨医科大学 降钙素在制备防治支架内再狭窄药物中的应用、药物涂层支架及制备方法

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WO1999051241A1 (en) * 1998-04-08 1999-10-14 Smithkline Beecham Corporation Calcilytic compounds and method of use

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WO1999051241A1 (en) * 1998-04-08 1999-10-14 Smithkline Beecham Corporation Calcilytic compounds and method of use

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CN1367687A (zh) 2002-09-04
CO5180628A1 (es) 2002-07-30
IL147875A0 (en) 2002-08-14
ECSP003590A (es) 2002-02-25
BR0012921A (pt) 2002-06-18
ZA200200784B (en) 2003-01-29
HUP0202167A2 (en) 2002-10-28
CZ2002360A3 (cs) 2002-10-16
TR200200278T2 (tr) 2002-06-21
HUP0202167A3 (en) 2006-07-28
EP1200076A1 (en) 2002-05-02
WO2001008673A1 (en) 2001-02-08
MXPA02001204A (es) 2004-05-21
CA2380081A1 (en) 2001-02-08
JP2003505502A (ja) 2003-02-12
PE20010459A1 (es) 2001-06-11
KR20020016928A (ko) 2002-03-06
HK1046238A1 (zh) 2003-01-03
UY26265A1 (es) 2001-03-16

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