Classifications

• • 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

• 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et al (1999) J Bone Miner Res In press, Nilsson, L.O., et al (1999) J Clin Endocrinol Metab 84, 370-373; Windahl own unpublished results).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.
• 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.
• 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.
• 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 mammal may be male or female and is preferably pre-pubesent.
• an ER ⁇ selective antagonist in the preparation of a medicament for the treatment of a growth disorder.
• 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.
• 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 ⁇ .
• Fig. 8 illustrates the effects of androgens in the male mouse skeleton.
• AR androgen receptor
• ER ⁇ estrogen receptor- ⁇
• ER ⁇ estrogen receptor- ⁇ .
• 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).
• 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).
• 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/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).
• 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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