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WO2000076529A2 - Recepteur d'oestrogenes - Google Patents

Recepteur d'oestrogenes Download PDF

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Publication number
WO2000076529A2
WO2000076529A2 PCT/GB2000/002283 GB0002283W WO0076529A2 WO 2000076529 A2 WO2000076529 A2 WO 2000076529A2 GB 0002283 W GB0002283 W GB 0002283W WO 0076529 A2 WO0076529 A2 WO 0076529A2
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WO
WIPO (PCT)
Prior art keywords
erα
erko
derko
antagonist
agonist
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PCT/GB2000/002283
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English (en)
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WO2000076529A3 (fr
Inventor
Claes Ohlsson
Jan Ake Gustafsson
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Karo Bio Ab
Dean, John, Paul
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Priority to EP00940530A priority Critical patent/EP1185287A2/fr
Priority to AU55454/00A priority patent/AU5545400A/en
Priority to CA002376441A priority patent/CA2376441A1/fr
Publication of WO2000076529A2 publication Critical patent/WO2000076529A2/fr
Publication of WO2000076529A3 publication Critical patent/WO2000076529A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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

Definitions

  • This invention relates to estrogen receptors and, particularly though not exclusively, to the effect of estrogen receptors and their ligands/modulators on the regulation of growth and bone-related parameters.
  • Orchidectomy decreases longitudinal growth and radial cortical growth in the long bones of rodents (Turner, R. T et al (1990) J. Orthop Res. 8, 612-617; Turner, R. T et al (1989) J Bone Miner Res. 4, 557-563; Sandstedt, J et al (1994) Endocrinology 135, 2574-2580; Ornoy, A. et al (1994) Bone Miner 24, 43-58). Furthermore, androgen treatment stimulates growth in orchidectomized growing rats and mice (Turner R. T. et al (1990) supra; Ornoy, A.
  • orchidectomy In addition to the growth-related effects of gonadal deficiency, orchidectomy also decreases bone mass in adult rodents (Turner R. T et al (1989) supra; Vanderschueren, D et al (1997) supra; Koh, E T et al (1996) Magnes Res. 9, 13-21). This effect is at least partly dependent on the androgen receptor as treatment with non-aromatizable androgens restores bone mass (Vanderschueren D et al (1992) supra; Wakley, G. K. et al ) 1991) J Bone Miner Res. 6, 325-330). On the other hand several clinical studies have demonstrated a strong relationship between serum estrogen levels and BMD in males (Slemenda, C. W.
  • ER ⁇ is expressed in growth plate chondrocytes and osteoblasts, indicating a possible role for ER ⁇ in the regulation of longitudinal bone growth and/or adult bone metabolism (Onoe, Y., et al (1997) Endocrinology 138, 4509-4512, Arts, J., Kuiper, G.G., et al (1997) Endocrinology 138, 5067-5070, Vidal, O., et al (1999) J Bone Miner Res In press, Nilsson, L.O., et al (1999) J Clin Endocrinol Metab 84, 370-373; Windahl own unpublished results).
  • mice devoid of functional ER ⁇ protein have recently generated mice devoid of functional ER ⁇ protein and reported that ER ⁇ is essential for normal ovulation efficiency, but is not essential for female or male sexual development, fertility, or lactation (Krege, J.H., et al (1998) Proc Natl Acad Sci US A 95, 15677-15682).
  • ER ⁇ and ER ⁇ have almost identical DNA-binding domains and studies in vitro have demonstrated that the two receptors have similar affinities for estrogenic compounds (Kuiper, G.G. et al (1996) Proc Natl Acad Sci U S A 93, 5925-5930, Kuiper, G.G., et al (1997) Endocrinology 138, 863-870, Tremblay, G.B., et al (1997) Mol Endocrinol 11, 353-365).
  • the amino-acid sequence of ER ⁇ differs from ER ⁇ in the N- and C-terminal trans-activating regions.
  • ER ⁇ may be distinct from that of ER ⁇ (Paech, K, et al (1997) Science 277, 1508-1510).
  • a differential tissue distribution of estrogen receptors may be important for mediating tissue specific responses to estrogens (Kuiper, G.G., and Gustafsson, J.A. (1997) FEBS Lett 410, 87-90).
  • the unique transactivating domains of the two receptor subtypes, in combination with differential tissue-distribution, or differential cell-type distribution within a tissue could be important factors to determine the estrogen response in target tissues.
  • the hormone testosterone is required for the pubertal growth spurt and the acquisition of normal bone density in mammals. These effects of testosterone may be direct via stimulation of the androgen receptor, or indirect via aromatisation of testosterone and thereafter stimulation of estrogen receptors. In the present study, the inventors have looked at the role of estrogen receptor subtypes for pubertal growth and adult bone metabolism in male mammals, particularly male mice.
  • the effect of androgens on the male skeleton may either be direct via a stimulation of androgen receptors or indirect via aromatization of androgens into estrogen and thereafter stimulation of estrogen receptors.
  • Possible direct effects of androgens are illustrated by skeletal abnormalities in androgen resistant humans and rodents (Bertelloni. S. et al (1998) Horm. Res. 50, 309-314, Vanderschueren, D. et al (1993) J. Bone. Miner. Res. 8, 801-809).
  • the effect of androgens on the male skeleton at least partly, is dependent on the conversion of androgens into estrogen.
  • Ornoy et al showed that orchidectomy in mice decreases growth plate area measured in the proximal tibia and that low-dose estrogen treatment increases the same parameter (Ornoy, A et al (1994) supra). These findings demonstrate that physiological levels of estrogen have a stimulatory effect on longitudinal growth in male rodents. Similarly, estrogens are required for the pubertal growth spurt in boys (MacGillivray, M. H. et al (1998) Horm. Res. 49 Suppl 1, 2-8). Estrogen regulates final height in humans by a stimulatory effect on the pubertal growth spurt, followed by closure of the epiphyseal growth plates at the end of puberty. In humans with estrogen deficiency or estrogen resistance growth plate fusion never occurs.
  • ERKO and DERKO mice demonstrated a decreased diaphyseal cross sectional area and periosteal circumference of femur, resulting in a pronounced decrease of the area moment of inertia.
  • the area moment of inertia is normally proportional to the mechanical strength of the bone determined by three-point-bending (Ferretti, J. L. et al (1996) Bone 18, 97-102).
  • the maximal load was decreased in male ERKO mice but it was not decreased more than suggested by the changes in area moment of inertia. Therefore, the amount of bone, but not the mechanical quality of the bone, was decreased in ER ⁇ inactivated male mice.
  • Aromatase inhibition of male rats resulted in a small decrease in trabecular BMD (Vanderschueren, D. et al (1997) supra).
  • neither the pQCT technique nor bone histomorphometry detected any significant changes in cancellous bone density in male ERKO, BERKO or DERKO mice.
  • our experiments indicate that neither ER ⁇ nor ER ⁇ is essential for the maintenance of cancellous bone mass in the male mouse. This finding raises the question whether other estrogen receptor subtypes exist or whether other hormones may compensate for estrogen resistance in the skeleton of male DERKO mice. Androgens prevent cancellous osteopenia in orchidectomized rats.
  • Bone loss following gonadal deficiency is normally associated with increased bone turnover.
  • osteocalcin a marker for bone formation
  • This finding and the pronounced cortical osteopenia seen in ERKO and DERKO males led us to seek other explanations to the skeletal phenotype in these mice.
  • Over-all size and cortical radial growth are parameters that are highly sensitive to changes in the GH/IGF-I axis (Andreassen, T. T. (1995) J. Bone. Miner Res. 10 1057-1067, Ohlsson, C. et al (1998) Endocr. Rev. 19 55-79; Rosen, H. N. et al (1995) J. Bone. Miner.
  • GH and IGF-I are known to increase serum osteocalcin (Ohlsson. C. et al (1998) Endocr. Rev. 19, 55-79). Therefore, the decreased serum osteocalcin levels in male ERKO mice may be caused by reduced serum IGF-I levels. This is also supported by the finding that aromatase inhibited male rats have decreased serum IGF-I levels and reduced levels of serum osteocalcin (Vanderschueren, D. et al (1997) supra). An effect of estrogen on the GH/IGF-I axis in males is also supported by several clinical as well as experimental studies. Circulating GH and IGF-I concentrations increase during normal male puberty (Miller, J. D. et al (1982) J. Clin.
  • Endocrinol Metab. 62, 159-164 The mechanism whereby testosterone interacts with the somatotropic axis may either be direct, mediated by androgen receptors, or indirect through the action of estrogen on estrogen receptors.
  • estrogen mediates the effects of testosterone on the somatotropic axis has been suggested in a previous study showing a significant correlation between circulating levels of estrogen, but not testosterone, and GH secretion in men (Ho. K. Y. et al (1987) J. Clin. Endocrinol Metab. 64, 51-58).
  • testosterone plays an important role in the modulation of the somatotropic axis in adulthood and this effect is, at least partly, dependent on the conversion of testosterone to estrogen (Weissberger, A. J. et al (1993) J. Clin. Endocrinol. Metab 76, 1407-1412).
  • some of the skeletal effects seen in ER ⁇ inactivated male mice may be due to an inhibition of the GH IGF-I axis.
  • a method of treating growth disorders in a mammal comprising treating the mammal with an ER ⁇ -specific agonist.
  • a method of treating growth disorders in a mammal comprising treating the mammal with an ER ⁇ -specific antagonist.
  • the ER ⁇ ligand/modulator used in the method of the invention may be a SERM (Selective Estrogen Receptor Modulator) i.e a compound having a tissue-selective mixed agonist/antagonist activity.
  • SERMs include tamoxifen, raloxifene, drolixifene and tamoxifen methiodide.
  • the mammal may be male or female and is preferably pre-pubesent.
  • the ER ⁇ agonist or antagonist used in the method may have a binding affinity of less than lOnM for ER ⁇ .
  • the ER ⁇ agonist or antagonist has a binding affinity of 0.0001 to 10 nM for ER ⁇ .
  • an ER ⁇ selective agonist in the preparation of a medicament for the treatment of a growth disorder.
  • an ER ⁇ selective antagonist in the preparation of a medicament for the treatment of a growth disorder.
  • the ER ⁇ antagonist may have a binding affinity of ER ⁇ of less than 10 nM, preferably 0.0001 to 10 nM.
  • a pharmaceutical composition suitable for treating or preventing growth disorders in a mammal comprising an ER ⁇ antagonist or agonist.
  • the ER ⁇ agonist or antagonist has a binding affinity for ER ⁇ of less than 10 nM, most preferably 0.0001 to 10 nM.
  • compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or caster oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and or flavoring and/or colouring agents may be added.
  • a method of selecting compounds for the regulation of body growth in mammals comprising selecting a compound on the basis of its ability to antagonise agonist-dependent ER ⁇ activity.
  • a method of selecting compounds for the use in the treatment of growth disorders comprising testing the compound in a mammal which is wholly or partially ER ⁇ deficient or in cells derived from such an animal.
  • a method of treating a bone mineral density disorder in a mammal comprising treating the mammal with an ER ⁇ -specifc agonist.
  • the invention provides a method of treating a bone mineral density disorder in a mammal, the method comprising treating the mammal with an ER ⁇ -specific antagonist.
  • the ER ⁇ -specific ligand modulator may be a SERM, the mammal may be a male or female and may be pre-pubesent.
  • the ER ⁇ agonist or antagonist may have a binding affinity of less than 10 nM, preferably 0.0001 to 10 nM or ER ⁇ .
  • the invention also provides the use of an ER ⁇ selective agonist in the preparation of a medicament for the treatment of a bone mineral density disorder.
  • the invention provides the use of an ER ⁇ selective antagonist in the preparation of a medicament for the treatment of a bone mineral density disorder.
  • the invention also provides a pharmaceutical composition suitable for treating or preventing bone mineral density disorders in a mammal, the composition comprising an ER ⁇ antagonist or agonist.
  • the invention also provides a method of selecting compounds for the regulation of bone mineral density in mammals, the method comprising selecting a compound on the basis of its ability to antagonise agonist-dependent ER ⁇ activity.
  • compounds are selected for the regulation of adult bone mineral density disorders.
  • Fig 1 shows the results of experiments on weight gain in male mice
  • Fig, 2 illustrates the body weight in wild type (WT), ERKO, BERKP and DERKO mice at different ages.
  • Fig. 5 shows the results of tests on bone mineral density in rats.
  • Fig. 8 illustrates the effects of androgens in the male mouse skeleton.
  • AR androgen receptor
  • ER ⁇ estrogen receptor- ⁇
  • ER ⁇ estrogen receptor- ⁇ .
  • mice Male double heterozygous (ER ⁇ + " ⁇ + " ) mice were mated with female double heterozygous (ER ⁇ + ⁇ + ) mice resulting WT, ERKO, BERKO and DERKO offspring. All mice were of mixed C57BL/65/129 backgrounds.
  • mice Male wild type (WT) as well as estrogen receptor ⁇ -/- (B ⁇ RKO) mice demonstrated a pubertal growth spurt as measured with body weight gain/day (Fig. 1) In contrast, no pubertal growth spurt was seen in estrogen receptor ⁇ -/- mice ( ⁇ RKO) or in mice devoid of both estrogen receptors (D ⁇ RKO).
  • the length of the femur was unchanged at the prepubertal stage (Fig 3A, day 31, one-way ANOVA). Thereafter ⁇ RKO and D ⁇ RKO demonstrated a gradual decrease in growth rate, resulting in a decreased femoral length at the adult stage ( ⁇ RKO -5.7%, D ⁇ RKO -4.4% versus WT, Fig 3A, 5A).
  • the decreased growth of the long bones in ERKO and DERKO was associated with a decreased growth plate width measured in the proximal tibia (Fig 3C).
  • the CR length was also decreased in ERKO and DERKO compared with WT (Fig 3B).
  • Mid-diaphyseal pQCT scans of femora and tibiae were performed to determine the cortical volumetric bone mineral density (volumetric BMD), cortical cross sectional area, periosteal and endosteal circumference and the cross sectional moment of inertia.
  • the mid-diaphyseal region of femora and tibiae in mice contains only cortical bone.
  • Metaphyseal pQCT scans of left femora and tibiae were performed to measure trabecular volumetric BMD.
  • the scan was positioned in the metaphysis at a distance from the distal growth plate corresponding to 4 % of the total length of the femur (an area containing cortical as well as trabecular bone).
  • the trabecular bone region was defined by setting an inner threshold to 45% of the total area.
  • the inter-assay coefficients of variation (CV) for the pQCT measurements were less than 2%.
  • the DXA technique gives the areal BMD whereas the pQCT gives the true volumetric BMD. Therefore a factor regulating the outer dimensions of a bone, will affect the areal BMD (DXA) but not the volumetric BMD (pQCT).
  • Bone Histomorphometry The areas of trabecular bone within a reference area of the proximal tibia were measured in sections stained with Hematoxylin/Eosin. Measurements were performed on printed copies by point counting using a square lattice (1 and 2 cm). Three fields of vision on three sections from each animal were used for the analysis. Data is presented as the ratio of trabecular bone volume (BV) to total volume (TV).
  • Serum IGF-1 levels were measured by double antibody IGF binding protein-blocked radio immunoassay according to Blum and Breier (31).
  • Dynamic measurements were first analysed by a two-way analysis of variance (A OVA) followed by Student Newman Keuls multiple range test. Static measurements (at the time of sacrifice) were first analysed by one-way ANOVA followed by Student Newman Keuls multiple range test.
  • BMC (g) and areal BMD (mg/mm 2 ) were measured with DXA.
  • the BMC (A) and BMC/Body weight (B) of the whole skeleton (total), femur, spine and cranium were measured using DXA technique as described in Methods. Values are given as means ⁇ SEM. Data at different ages were first analysed by a two-way analysis of variance followed by Student Newman Keuls multiple range test. P values versus WT mice are indicated. BERKO demonstrated unchanged BMC and areal BMD (Fig 5 A, table 1).
  • Femur BMD (mg/cm 2 ) Day 31 35.1 ⁇ 0.9 33.3 ⁇ 0.5 34.5 ⁇ 0.7 35.5 ⁇ 1.2
  • BMC/body weight was calculated for the whole skeleton and for individual bones.
  • BMC/body weight was decreased in ERKO (-18%) and DERKO (-22%) when compared to WT. This was also the case for femur (ERKO -20; DERKO -19%) and spine (ERKO -21%; DERKO -18%; Fig 5B).
  • Cortical endosteal circumference (mm) 4.31 ⁇ 0.13 3.89 ⁇ 0.05* 4.28 ⁇ 0.09 4.0210.11 Values are given as means 1 SEM. Data were first analysed by a one-way analysis variance followed by followed by Student Newman Keuls multiple range test. * p ⁇ 0.05. ** p ⁇ 0.01 versus WT.
  • BV/TV trabecular bone volume/total volume
  • Cortical bone parameters were studied in detail in mid-diaphyseal pQCT scans of femora and tibiae (Table 2, Fig 6B and data not shown).
  • the cortical BMC in the mid-diaphyseal section of femur was decreased in ERKO (-14%) and DERKO (-14%) compared with WT and this decrease was mainly due to a decreased cross-sectional bone area whereas cortical volumetric density was unchanged (Table 2).
  • the decrease in cross sectional area in ERKO and DERKO was associated with decreased periosteal and endosteal circumference (Fig 6B and Table 2).
  • Osteocalcin a marker of bone formation was measured in serum at 110 days of age. Osteocalcin was decreased in ERKO (Osteocalcin -25%, Table 4) and a tendency to decrease was seen in DERKO (Osteocalcin -9%, Table 4).
  • IGF-I (ng/ml) 337136 25018* 313112 26416
  • the weights of several other organs were measured to see if the effect on the skeleton in ERKO and DERKO was tissue specific. To compare the relative growth of different organs the individual organ weights were divided with the total body weight. The weights of the liver, kidney, brain and testis were not significantly changed in any group. However, the weights of heart and lung were decreased in the ERKO compared with WT (heart -15%, lung -17%), Fig 7). In the results shown in Fig. 7, values are given as means 1 SEM. Data were first analysed by a one-way analysis of variance followed by Student Newman Keuls multiple range test. * p ⁇ 0.05 versus WT. These experiments demonstrate that ER ⁇ but not ER ⁇ is involved in the regulation of pubertal growth and adult bone mineral density in male mammals such as mice.

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Abstract

Les androgènes régulent le squelette du mâle directement, par la stimulation de récepteurs d'androgènes, et indirectement, par l'aromatisation d'androgènes et par leur transformation en oestrogènes suivie de la stimulation des récepteurs d'oestrogènes (RO). Afin d'étudier dans le détail l'importance relative des sous-types de récepteurs oestrogènes dans la régulation du squelette mâle, on a comparé les phénotypes du squelette des souris de type sauvage (TS), ROα, Knock-out (ROKO), ROβ Knock-out (BROKO) et ROα/β Double Knock-out (DROKO). ROKO et DROKO ont un poids corporel réduit et une croissance longitudinale d'os moins importante. En outre, ROKO et DROKO mais pas BROKO manifestent une diminution prononcée de la teneur minérale dans les os longs et le squelette axial. Cette diminution de la teneur minérale des os est due à l'ostéopénie corticale causée par une croissance radicale des os moins importante. Des tests mécaniques ont montré que le fémur des ROKO est plus faible, ce qui est une conséquence du changement des dimensions de l'os cortical. Dans aucun groupe, on n'a remarqué aucun changement notable au niveau de la densité osseuse trabéculaire. Les ROKO ont manifesté des taux de sérum réduits en ostéocalcine et en IGF-I. En outre, les taux de sérum en IGF-I ont été corrélés avec la plupart des changements au niveau du squelette que l'on a vu chez DROKO et ROKO. On peut en conclure que les phénotypes squelettiques des DROKO et des ROKO sont similaires et peuvent être clairement distingués du TS et des BROKO. Ainsi, c'est le récepteur ROα mais non pas celui ROβ qui sert de médiateur de l'effet de l'oestrogène dans le squelette de la souris.
PCT/GB2000/002283 1999-06-11 2000-06-12 Recepteur d'oestrogenes WO2000076529A2 (fr)

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EP00940530A EP1185287A2 (fr) 1999-06-11 2000-06-12 Recepteur d'oestrogenes
AU55454/00A AU5545400A (en) 1999-06-11 2000-06-12 Estrogen receptor
CA002376441A CA2376441A1 (fr) 1999-06-11 2000-06-12 Recepteur d'oestrogenes

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6794403B2 (en) 2001-12-05 2004-09-21 Wyeth Substituted benzoxazoles as estrogenic agents
US6835745B2 (en) 2002-01-15 2004-12-28 Wyeth Phenyl substituted thiophenes as estrogenic agents
US7354927B2 (en) 2004-09-07 2008-04-08 Wyeth 6H-[1]benzopyrano[4,3-b]quinolines and their use as estrogenic agents

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL109990A (en) * 1993-06-21 1999-06-20 Lilly Co Eli Materials and methods for screening anti-osteoporosis agents
EP0800530A4 (fr) * 1994-07-20 1998-12-02 Celtrix Pharma Complexe igf/igfbp destines a favoriser la formation osseuse et a reguler le remodelage osseux
HN1996000101A (es) * 1996-02-28 1997-06-26 Inc Pfizer Terapia combinada para la osteoporosis
WO1998025623A1 (fr) * 1996-12-09 1998-06-18 Merck & Co., Inc. Procedes et compositions destines a prevenir et a traiter la perte osseuse

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6794403B2 (en) 2001-12-05 2004-09-21 Wyeth Substituted benzoxazoles as estrogenic agents
US7129258B2 (en) 2001-12-05 2006-10-31 Wyeth Substituted benzoxazoles as estrogenic agents
US7148247B2 (en) 2001-12-05 2006-12-12 Wyeth Substituted benzoxazoles as estrogenic agents
US7531564B2 (en) 2001-12-05 2009-05-12 Wyeth Substituted benzoxazoles as estrogenic agents
US6835745B2 (en) 2002-01-15 2004-12-28 Wyeth Phenyl substituted thiophenes as estrogenic agents
US7354927B2 (en) 2004-09-07 2008-04-08 Wyeth 6H-[1]benzopyrano[4,3-b]quinolines and their use as estrogenic agents

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