WO2013024311A1 - Amidoxime derivatives for the prevention and/or treatment of muscle atrophy - Google Patents
Amidoxime derivatives for the prevention and/or treatment of muscle atrophy Download PDFInfo
- Publication number
- WO2013024311A1 WO2013024311A1 PCT/HU2012/000070 HU2012000070W WO2013024311A1 WO 2013024311 A1 WO2013024311 A1 WO 2013024311A1 HU 2012000070 W HU2012000070 W HU 2012000070W WO 2013024311 A1 WO2013024311 A1 WO 2013024311A1
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- WIPO (PCT)
- Prior art keywords
- formula
- amidoxime
- muscle
- muscle atrophy
- hydrogen atom
- Prior art date
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- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
Definitions
- the invention refers to the use of an amidoxime derivative of formula I
- Ar represents a pyridyl group
- A is a valence bond
- Ri stands for a hydrogen atom
- R2 represents a hydrogen atom
- R 3 stands for a group of formula
- R 4 represents a hydrogen atom
- R 5 is a 5-7-membered saturated heterocyclic group containing a nitrogen atom
- Ar represents a phenyl group
- Ri is a hydrogen atom
- R2 represents a group of formula
- R 4 represents a hydrogen atom
- R 5 stands for a 5-7- membered saturated heterocyclic group containing a nitrogen atom
- R3 is hydrogen atom
- R2 represents a group of formula
- R 4 represents a hydrogen atom
- R 5 stands for a 5-7- membered saturated heterocyclic group containing a nitrogen atom
- Ri represents a carbonyl group
- R 3 is a valence bond between the carbon atom of the carbonyl group and the oxygen atom adjacent to R3,
- the muscle mass is determined by the ratio of synthesis and decomposition of muscle protein. In various conditions causing muscle atrophy, in addition to ageing, an activation of a complex biochemical and transcription system can be observed leading to the expression of an atrogenic set of genes [Glass, DJ. Molecular mechanisms modulating muscle mass. (2003) Trends Mol Med., 9(8):344-50] ⁇ Cao PR, Kim HJ, Lecker SH Ubiquitin-protein ligases in muscle wasting. (2005) Int J Biochem Cell Biol.
- Atrogenic genes belongs to the ubiquitin-proteasome system allowing the selective degradation of regulating and structural proteins [Lecker SH, Goldberg AL, Mitch WE.: Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. (2006) J Am Soc Nephrol. ; 17(7): 1807-19].
- PGC-1 peroxisome proliferator-activated receptor gamma coactivator transcription factors stimulated by the physical activity protect against muscle atrophy and they are effective mainly through the inhibition of Fox03 and NF- ⁇ [Jeffrey J. Brault et al., (2010) J. Biol. Chem. 285:19460-19471].
- the aim of the invention is the provision of a pharmaceutical composition for the prevention and/or treatment of muscle atrophy.
- amidoxime derivatives of formula I are known compounds.
- Amidoxime derivatives of formula I, wherein R-i , R 2 and R 3 are as defined in section a) above, can be prepared using the process described in US Patent No. 4,187,220.
- the other amidoxime derivatives of formula I can be prepared by the processes described in the PCT application published as WO 01/70674.
- amidoxime derivatives of formula I inhibit the PARP enzyme.
- BGP-15 of formula II Several pharmacological effects of one of them, BGP-15 of formula II, are known.
- BGP-15 for the treatment of diabetic angiopathy is known from US Patent No. 4, 87,220 mentioned above.
- US Patent No. 6,306,878 refers to a method for the protection of the mitochondrial genome and/or mitochondrion from damage leading to myopathies and neurodegenerative diseases which comprises administering an effective non-toxic dose to a patient susceptible to such a damage of an amidoxime acid derivative including BGP-15.
- US Patent No. 6,458,371 refers to a composition comprising 0.1-30 % of a hydroximic acid derivative such as BGP-15 and a carrier.
- the composition is suitable for reducing the incidence of photodamage by radiation with UV-B.
- US Patent No. 6,884,424 refers to a method for preventing actinic keratosis by applying a hydroximic acid derivative e.g. BGP-15 to the affected skin surface.
- a hydroximic acid derivative e.g. BGP-15
- US Patent No. 6,451 ,851 refers to a method of treating a patient suffering from a viral infection comprising administering to the patient a pharmaceutically effective amount of a known antivirally active agent together with a hydroximic acid derivative e.g. BGP-15.
- US Patent No. 6,440,998 refers to a pharmaceutical composition having antitumour activity with reduced side effect comprising cisplatin or carboplatin and a hydroximic acid derivative such as BGP- 5.
- US Patent No. 6,656,955 refers to a pharmaceutical composition having antitumour activity with reduced side effect comprising paclitaxel or docetaxel and a hydroximic acid derivative such as BGP-15.
- US Patent No. 6,720,337 refers to a pharmaceutical composition having antitumour activity with reduced side effect comprising oxaliplatin and a hydroximic acid derivative such as BGP-15.
- 6,838,469 refers to a pharmaceutical composition having antitumour activity with reduced side effect comprising pyrimidine derivatives and BGP-15.
- PCT Application published under No. WO 00/07580 disclosed experimental data for the antidiabetic effect of BGP- 15 in the treatment of type 1 diabetes mellitus.
- WO 03/007951 refers to a pharmaceutical combination of hydroximic acid derivatives such as BGP-15 and an antidiabetic or anti- hyperlipidemic active agent for the prevention or treatment of a prediabetic state, metabolic X-syndrome or diabetes mellitus as well as disorders wich are associated with the states listed above, namely endogenic metabolic disorders, insulin resistance, dis!ipidemia, alopecia, diffuse effluvium and/or female endocrine disorders based on androgenic preponderance.
- PCT Application published under No. WO 2005/122678 refers to the use of BGP-15 in a pharmaceutical composition having prokinetic effect (i.e. inducing activity in the stomach and intestines).
- PCT Application published under No. WO 2006/079910 refers to the use of BGP-15 for the treatment of lesions in the oral cavity, especially periodontal disease.
- European Patent No. 2 089 031 BGP-15 can be employed for reducing overweight or obesity.
- European Patent No. 2 089 032 BGP-15 reduces the side effect of known antipsychotics, antidepressants and antiepileptics leading to overweight or obesity.
- the invention provides the use of an amidoxime derivative of formula I or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition for the prevention and/or treatment of muscle atrophy.
- the invention provides a method for the prevention and/or treatment of muscle atrophy which comprises administering to a patient exposed to or suffering from muscle atrophy an effective non-toxic dose of an amidoxime derivative of formula I or a pharmaceutically suitable acid addition salt thereof.
- R 5 under a 5-7-membered saturated heterocyclic group containing a nitrogen atom a pyrrolidyl group, piperidyl group or hexamethylene-imino group is meant.
- a pharmaceutically suitable acid addition salt is an acid addition salt formed with a pharmaceutically acceptable inorganic or organic acid such as a hydrochloride, acetate, fumarate, maleate etc.
- a preferred subgroup of the amidoxime derivatives of formula I consists of the compounds, wherein in the formula Ri, R 2 and R3 are as defined in section a) above.
- An especially preferred compound in this subgroup is 0-(3-piperidino-2- hydroxy-1-propyl)nicotinic amidoxime (abbreviated as BGP-15) which is suitably used in the form of the dihydrochloride thereof of formula II
- Another preferred subgroup of the amidoxime derivatives of formula I consists of the compounds, wherein in the formula R-i, R 2 and R 3 are as defined in sections b) and bi) above.
- An especially preferred compound in the subgroup is N-[3- (hexamethyleneimino)-2-hydroxypropyl]cinnamic amidoxime (abbreviated as NG-094) of formula III
- the dihydrogen maleate of NG-094 is used.
- a further preferred subgroup of the amidoxime derivatives of formula I consists of the compounds, wherein in the formula R-i , R 2 and R3 are as defined in sections b) and b 2 ) above, thus, the compounds contain an oxadiazolin ring.
- An especially preferred compound in this subgroup is 3-styryl-4-[3- (hexamethylene-imino)-2-hydroxypropyl]-A 2 -1 ,2,4-oxadiazolin- 5-one (abbreviated as NG-50) of formula IV
- the hydrochloride of NG-50 is used.
- - muscle atrophy developed due to inactivity or immobilization e.g. fracture of limbs, treatment with a respirator machine, treatment in an intensive care unit, a physical state requiring keeping to bed for a long time etc., - muscle atrophy of neuronal origin (damage of neurons, degeneration, muscle atrophy caused by neuromuscular synapsis inhibitors),
- any composition for human or veterinary use is meant, wherein the composition comprises, in addition to the active ingredient i.e. an amidoxime derivative of formula I or a pharmaceutically suitable acid addition salt thereof, one or more carrier(s) conventionally employed in such compositions.
- the pharmaceutical composition may include any dosage form suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid.
- the solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film- coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly(vinylpyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethylene glycol), silica etc.; wetting agents such as sodium laurylsulfate etc. as the carrier.
- Capsules may contain the pure active agent without any carrier, other dosage forms contain, in addition to the active agent, one or more carrier(s).
- the liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propylene glycol, ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
- suspending agents such as gelatine, carboxymethylcellulose etc.
- emulsifiers such as sorbitane monooleate etc.
- solvents such as water, oils, glycerol, propylene glycol, ethanol etc.
- preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
- compositions suitable for parenteral administration consist of sterile solutions of the active ingredients, in general.
- the sterile solution may contain, in addition to the active agent, pH control agents and osmolarity control agents, preservatives, surfactants etc.
- ointments for example, ointments, solutions, creames, transdermal patches etc. can be used.
- Dosage forms listed above as well as other dosage forms are known per se, see e.g. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).
- the pharmaceutical composition contains dosage unit, in general.
- the daily dose amounting generally to 1-1000 mg of amidoxime derivative of formula I or a pharmaceutically suitable acid addition salt thereof can be administered in one or more portions.
- the actual dosage depends on many factors and is determined by the doctor.
- the pharmaceutical composition is prepared by admixing the active ingredient to one or more carrier(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se.
- Useful methods are known from the literature, e.g. Remington's Pharmaceutical Sciences mentioned above.
- Muscle atrophy developed by cutting the nerve in the muscle is a rapid and robust model widely used for the examination of muscle atrophy in vivo.
- the atrophy of the muscle of one of the hind legs is achieved usually by cutting the sciatic nerve (nervus ischiadicus) [Medina, R., Wing SS., Goldberg AL: Increase in levels of polyubiquitin and proteasome mRNA in skeletal muscle during starvation and denervation atrophy. Biochem. J. ,(1995), 308:631-7].
- the experiments were carried out in male Wistar rats having a body mass of 150-200 g in narcosis with pentobarbital.
- the sciatic nerve was exposed by excising the skin of 1-2 cm growth at about 1 cm from the spinal column and a 5-10 mm section of the nerve was cut out. The wound was sutured.
- Half of the animals was treated with 20 mg/kg and 60 mg/kg doses of BGP-15, respectively, 3 hours after the surgical intervention, then once daily for 8 or 9 days, orally.
- the control animals obtained a similar treatment with the same amount of the carrier and tap water.
- On day 8 or 9 of the experiment the animals were overnarcotized with pentobarbital, then the gastrocnemius, soleus and. tibial anterior muscles were isolated from both legs, weighed and frozen in liquid nitrogen. The rate of muscle atrophy developed by denervation was characterized by the weight loss in comparison with the weight of the corresponding muscle on the opposite side, in percentage. Results
- the treatment reduced the muscle loss caused denervation by 13-38 %.
- Lidocaine induced rat hind limb immobilization was perfomed by the slight modification of the method of L. Soderberg, H. Dyhre, et al. (Anesthesiology 2006; 104:110-21 Ultralong Peripheral Nerve Block by Lidocaine:Prilocaine 1 :1 Mixture in a Lipid Depot Formulation).
- Wistar rats weighing around 150-200g were anaesthetised with pentobarbital i.p.
- the right sciatic nerve was exposed through a 0.5 cm incision and blunt dissection of the gluteal muscles.
- the sciatic nerve was mobilized carefully and gently, then isolated with a nylon strip. Then ⁇ /IOOg bw 80% lidocaine was instilled over the nerve. After 5 min the nylon stripe was removed. A silk suture was used to close the muscle gap. Before tightening the suture 25pl/100g of the 30% solution was instilled on the nerve then the skin was closed.
- test compound(s) efficiently inhibit both the denervation and the insufficient function (anatomically intact nerve system) induced muscle loss.
Abstract
The invention refers to the use of an amidoxime derivative of formula (I) or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition for the prevention and/or treatment of muscle atrophy.
Description
AMIDOXIME DERIVATIVES FOR THE PREVENTION AND/OR TREATMENT OF MUSCLE ATROPHY
Field of the invention
The invention refers to the use of an amidoxime derivative of formula I
Ar— A— C— N— Ri
II I
N R2 I
I
OR3
wherein
a) Ar represents a pyridyl group,
A is a valence bond,
Ri stands for a hydrogen atom,
R2 represents a hydrogen atom,
R3 stands for a group of formula
OR4
wherein R4 represents a hydrogen atom, R5 is a 5-7-membered saturated heterocyclic group containing a nitrogen atom, or b) Ar represents a phenyl group,
A stands for a -CH=CH- group and
bi) Ri is a hydrogen atom,
R2 represents a group of formula
OR4
wherein R4 represents a hydrogen atom, R5 stands for a 5-7- membered saturated heterocyclic group containing a nitrogen atom,
R3 is hydrogen atom, or
b2) R2 represents a group of formula
OR4
wherein R4 represents a hydrogen atom, R5 stands for a 5-7- membered saturated heterocyclic group containing a nitrogen atom,
Ri represents a carbonyl group, R3 is a valence bond between the carbon atom of the carbonyl group and the oxygen atom adjacent to R3,
or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition for the prevention and/or treatment of muscle atrophy.
Background of the invention
The muscle mass and muscular strength are diminished, gradually, due to ageing [Karakelides, H. and Nair, K. S. (2005) Curr. Top Dev. Biol., 68, 123-148]. The role of several mechanisms has been pointed out in muscle atrophy connected with ageing [Doherty, T. J. et al., (1993) J. Appl. Physiol. 74, 868-874; Delbono, O. (2003) Aging Cell 2, 21-29]. The most important causal mechanism can be the loss of motoneurons or the reduction of neural connections [Brown, W. F.: A method for estimating the number of motor units in thenar muscles and the
changes in motor unit count with ageing. (1972) J. Neurol. Neurosurg. Psychiatry 35, 845-852; Brown, W. F. and Chan, K. .: Quantitative methods for estimating the number of motor units in human muscles. (1997) Muscle Nerve, 5, (suppl.) S70- S73]. The muscle mass is determined by the ratio of synthesis and decomposition of muscle protein. In various conditions causing muscle atrophy, in addition to ageing, an activation of a complex biochemical and transcription system can be observed leading to the expression of an atrogenic set of genes [Glass, DJ. Molecular mechanisms modulating muscle mass. (2003) Trends Mol Med., 9(8):344-50]\ Cao PR, Kim HJ, Lecker SH Ubiquitin-protein ligases in muscle wasting. (2005) Int J Biochem Cell Biol. 37(10):2088-97]. A part of the atrogenic genes belongs to the ubiquitin-proteasome system allowing the selective degradation of regulating and structural proteins [Lecker SH, Goldberg AL, Mitch WE.: Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. (2006) J Am Soc Nephrol. ; 17(7): 1807-19]. The expression of two E3 ubiquitin ligases: the„muscle RING-finger" 1 (MuRF1 ) and the „muscle atrophy F-box" (MAFbx; also named as Atrogin-1 ) is highly increased in various forms of muscle atrophy both in man and rodent [Bodine, S.C. et al., Identification of ubiquitin ligases required for skeletal muscle atrophy. (2001) Science., 294 (5547): 1704-8}. The important catabolic role of the two enzymes is supported by the fact that several types of muscle atrophy is interrupted by their inactivation. [Bodine, S.C. et al., cited reference; Glass DJ.:
Signaling pathways perturbing muscle mass. (2010) Curr Opin Clin Nutr Metab Care, 13(3):225-9].
It became obvious that also the lisosome autophagy system played an essential role in muscle atrophy [Sandri, M.: Autophagy in skeletal muscle. (2010) FEBS Lett, 584(7):1411- 6]. In addition, the coordinated function of the two systems (i.e. proteosome and autophagy) is more and more clear in various atrophy conditions [Mammucari, C. et al., FoxO3 controls autophagy in skeletal muscle in vivo. (2007) Cell Metab. 6(6):458-71·; Zhao, J. et al., Fox03 coordinate^ activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. (2007) Cell Metab. 6(6):472-83; Doyle, A. et al., Toll-like receptor 4 mediates lipopolysaccharide-induced muscle catabolism via coordinate activation of ubiquitin-proteasome and autophagy- lysosome pathways. (2011) FASEB J. 25(1):99-110]. A significant part of the genes induced during muscle atrophy is controlled by the Fox03 transcription factor that is activated in the atrophic muscle [Sandri, M. et al., (2004) Cell 117,399-412; Stitt, T. et al., (2004) Mol. Cell 14, 395-403]. Fox03 alone can also stimulate both the ubiquitin-proteosome and autophagy systems [Zhao, J. et al., (2007) Cell Metab. 6, 458-471] and induce the atrophy of the muscle fibre. The muscle specific ubiquitin ligases induced by Fox03 (i.e. Atroginl/MAFBx and MuRF1) are remarkably important in the proteolysis of muscle proteins [Bodine, S. C. et al., 2001, Science 294, 1704-1708] and, in the absence thereof, muscle atrophy caused by denervation is significantly inhibited. The role of NF-κΒ was
proved by several observations in different forms of muscle atrophy. Physical activity protects from the muscle atrophy caused by inactivity and some systemic diseases. Also PGC-1 (peroxisome proliferator-activated receptor gamma coactivator) transcription factors stimulated by the physical activity protect against muscle atrophy and they are effective mainly through the inhibition of Fox03 and NF-κΒ [Jeffrey J. Brault et al., (2010) J. Biol. Chem. 285:19460-19471].
In addition to the reduction of life expectancy, also the functional state and life quality is deteriorated by muscle atrophy. The most frequent causes of muscle atrophy comprise ageing, denervation, neuronal impairment, immobilization, starvation, chronic diseases (diabetes, renal diseases, tumours). The patients of intensive care units, especially the ones treated by respirator machines often experience serious muscle loss. Recent studies have proved that muscle atrophy and muscle weakness have been a grave complication of survivors of the intensive treatment, wherein the complication lasts for years [van Mook, W. N., Hulsewe-Evers, R. P.: Critical illness polyneuropathy. (2002) Curr Opin Crit Care. 8(4):302-10; Herridge, M. S. et al., One-year outcomes in survivors of the acute respiratory distress syndrome. (2003) N Engl J Med. 348(8):683-93; Cheung, A. M. et al., Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome. (2006) Am J Respir Crit Care Med. 174(5): 538-44]. A prolonged treatment with a respirator machine, steroid or neuromuscular inhibitor may lead to acute quadriplegic myopathy [Larsson L, (2008) Adv Exp Med Biol., 642:92-8] in
which nearly all the skeletal muscles are influenced by the muscle atrophy, consequently, the movement of the patients is not possible anymore.
The treatment and prevention of serious muscle atrophy have been unsolved up to now. The rehabilitation of the patients is very slow, the therapies employed for improving the movement are expensive and of low effectivity. There is no allowed pharmaceutical treatment for the prevention or curing of muscle atrophy.
The aim of the invention is the provision of a pharmaceutical composition for the prevention and/or treatment of muscle atrophy.
The amidoxime derivatives of formula I are known compounds. Amidoxime derivatives of formula I, wherein R-i , R2 and R3 are as defined in section a) above, can be prepared using the process described in US Patent No. 4,187,220. The other amidoxime derivatives of formula I can be prepared by the processes described in the PCT application published as WO 01/70674.
In general, the amidoxime derivatives of formula I inhibit the PARP enzyme. Several pharmacological effects of one of them, BGP-15 of formula II, are known.
The use of BGP-15 for the treatment of diabetic angiopathy is known from US Patent No. 4, 87,220 mentioned above.
US Patent No. 6,306,878 refers to a method for the protection of the mitochondrial genome and/or mitochondrion from damage leading to myopathies and neurodegenerative
diseases which comprises administering an effective non-toxic dose to a patient susceptible to such a damage of an amidoxime acid derivative including BGP-15.
US Patent No. 6,458,371 refers to a composition comprising 0.1-30 % of a hydroximic acid derivative such as BGP-15 and a carrier. The composition is suitable for reducing the incidence of photodamage by radiation with UV-B.
US Patent No. 6,884,424 refers to a method for preventing actinic keratosis by applying a hydroximic acid derivative e.g. BGP-15 to the affected skin surface.
US Patent No. 6,451 ,851 refers to a method of treating a patient suffering from a viral infection comprising administering to the patient a pharmaceutically effective amount of a known antivirally active agent together with a hydroximic acid derivative e.g. BGP-15.
US Patent No. 6,440,998 refers to a pharmaceutical composition having antitumour activity with reduced side effect comprising cisplatin or carboplatin and a hydroximic acid derivative such as BGP- 5. US Patent No. 6,656,955 refers to a pharmaceutical composition having antitumour activity with reduced side effect comprising paclitaxel or docetaxel and a hydroximic acid derivative such as BGP-15. US Patent No. 6,720,337 refers to a pharmaceutical composition having antitumour activity with reduced side effect comprising oxaliplatin and a hydroximic acid derivative such as BGP-15. US Patent No. 6,838,469 refers to a pharmaceutical composition having antitumour activity with reduced side effect comprising pyrimidine derivatives and BGP-15.
PCT Application published under No. WO 00/07580 disclosed experimental data for the antidiabetic effect of BGP- 15 in the treatment of type 1 diabetes mellitus.
PCT Application published under No. WO 03/007951 refers to a pharmaceutical combination of hydroximic acid derivatives such as BGP-15 and an antidiabetic or anti- hyperlipidemic active agent for the prevention or treatment of a prediabetic state, metabolic X-syndrome or diabetes mellitus as well as disorders wich are associated with the states listed above, namely endogenic metabolic disorders, insulin resistance, dis!ipidemia, alopecia, diffuse effluvium and/or female endocrine disorders based on androgenic preponderance.
PCT Application published under No. WO 2005/122678 refers to the use of BGP-15 in a pharmaceutical composition having prokinetic effect (i.e. inducing activity in the stomach and intestines).
PCT Application published under No. WO 2005/123049 refers to the use of BGP-15 for mitochondrial genesis i.e. to increase the number of mitochondria in the cells resulting in roborating effect.
PCT Application published under No. WO 2006/079910 refers to the use of BGP-15 for the treatment of lesions in the oral cavity, especially periodontal disease.
According to European Patent No. 2 089 031 BGP-15 can be employed for reducing overweight or obesity.
According to European Patent No. 2 089 032 BGP-15 reduces the side effect of known antipsychotics,
antidepressants and antiepileptics leading to overweight or obesity.
According to PCT Application published under No. WO 2009/074835 BGP-15 can be used for reducing the unfavourable psychiatric side effect of cannabinoid CBi antagonists such as rimonabant.
Summary of the invention
It was found that the above aim was achieved by a pharmaceutical composition comprising an amidoxime derivative of formula I or a pharmaceutically suitable acid addition salt thereof.
Thus, the invention provides the use of an amidoxime derivative of formula I or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition for the prevention and/or treatment of muscle atrophy.
Furthermore, the invention provides a method for the prevention and/or treatment of muscle atrophy which comprises administering to a patient exposed to or suffering from muscle atrophy an effective non-toxic dose of an amidoxime derivative of formula I or a pharmaceutically suitable acid addition salt thereof.
Description of preferred embodiments
In the definition of R5 under a 5-7-membered saturated heterocyclic group containing a nitrogen atom a pyrrolidyl group, piperidyl group or hexamethylene-imino group is meant.
A pharmaceutically suitable acid addition salt is an acid addition salt formed with a pharmaceutically acceptable
inorganic or organic acid such as a hydrochloride, acetate, fumarate, maleate etc.
A preferred subgroup of the amidoxime derivatives of formula I consists of the compounds, wherein in the formula Ri, R2 and R3 are as defined in section a) above. An especially preferred compound in this subgroup is 0-(3-piperidino-2- hydroxy-1-propyl)nicotinic amidoxime (abbreviated as BGP-15) which is suitably used in the form of the dihydrochloride thereof of formula II
II
Another preferred subgroup of the amidoxime derivatives of formula I consists of the compounds, wherein in the formula R-i, R2 and R3 are as defined in sections b) and bi) above. An especially preferred compound in the subgroup is N-[3- (hexamethyleneimino)-2-hydroxypropyl]cinnamic amidoxime (abbreviated as NG-094) of formula III
III
Suitably, the dihydrogen maleate of NG-094 is used.
A further preferred subgroup of the amidoxime derivatives of formula I consists of the compounds, wherein in the formula R-i , R2 and R3 are as defined in sections b) and b2) above, thus, the compounds contain an oxadiazolin ring. An especially preferred compound in this subgroup is 3-styryl-4-[3- (hexamethylene-imino)-2-hydroxypropyl]-A2-1 ,2,4-oxadiazolin- 5-one (abbreviated as NG-50) of formula IV
IV
Suitably, the hydrochloride of NG-50 is used.
In the description and claims under the term „muscle atrophy" a muscle atrophy of any origin, especially the following ones are meant:
- muscle atrophy caused by ageing,
- muscle atrophy developed due to inactivity or immobilization e.g. fracture of limbs, treatment with a respirator machine, treatment in an intensive care unit, a physical state requiring keeping to bed for a long time etc.,
- muscle atrophy of neuronal origin (damage of neurons, degeneration, muscle atrophy caused by neuromuscular synapsis inhibitors),
- muscle atrophy developed as a side effect of a steroid treatment,
- muscle atrophy caused by myopathies,
- muscle atrophy due to systemic diseases (diabetes, renal diseases, tumors, treatment of AIDS etc.).
Under a pharmaceutical composition" any composition for human or veterinary use is meant, wherein the composition comprises, in addition to the active ingredient i.e. an amidoxime derivative of formula I or a pharmaceutically suitable acid addition salt thereof, one or more carrier(s) conventionally employed in such compositions.
The pharmaceutical composition may include any dosage form suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid.
The solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film- coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly(vinylpyrrolidone) etc.; filling agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as magnesium stearate, talc, poly(ethylene glycol), silica etc.; wetting agents such as sodium laurylsulfate etc. as the carrier. Capsules may contain the pure active agent without any carrier, other dosage forms contain, in addition to the active agent, one or more carrier(s).
The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propylene glycol, ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
Pharmaceutical compositions suitable for parenteral administration consist of sterile solutions of the active ingredients, in general. The sterile solution may contain, in addition to the active agent, pH control agents and osmolarity control agents, preservatives, surfactants etc.
For local treatment, for example, ointments, solutions, creames, transdermal patches etc. can be used.
Dosage forms listed above as well as other dosage forms are known per se, see e.g. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).
The pharmaceutical composition contains dosage unit, in general. The daily dose amounting generally to 1-1000 mg of amidoxime derivative of formula I or a pharmaceutically suitable acid addition salt thereof can be administered in one or more portions. The actual dosage depends on many factors and is determined by the doctor.
The pharmaceutical composition is prepared by admixing the active ingredient to one or more carrier(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se. Useful methods are known from the
literature, e.g. Remington's Pharmaceutical Sciences mentioned above.
The following tests were carried out using the amidoxime derivatives of formula I.
Development of denervation muscle atrophy in rat
Muscle atrophy developed by cutting the nerve in the muscle is a rapid and robust model widely used for the examination of muscle atrophy in vivo. In rodents, the atrophy of the muscle of one of the hind legs is achieved usually by cutting the sciatic nerve (nervus ischiadicus) [Medina, R., Wing SS., Goldberg AL: Increase in levels of polyubiquitin and proteasome mRNA in skeletal muscle during starvation and denervation atrophy. Biochem. J. ,(1995), 308:631-7].
The experiments were carried out in male Wistar rats having a body mass of 150-200 g in narcosis with pentobarbital. The sciatic nerve was exposed by excising the skin of 1-2 cm growth at about 1 cm from the spinal column and a 5-10 mm section of the nerve was cut out. The wound was sutured. Half of the animals was treated with 20 mg/kg and 60 mg/kg doses of BGP-15, respectively, 3 hours after the surgical intervention, then once daily for 8 or 9 days, orally. The control animals obtained a similar treatment with the same amount of the carrier and tap water. On day 8 or 9 of the experiment the animals were overnarcotized with pentobarbital, then the gastrocnemius, soleus and. tibial anterior muscles were isolated from both legs, weighed and frozen in liquid nitrogen. The rate of muscle atrophy developed by denervation was characterized
by the weight loss in comparison with the weight of the corresponding muscle on the opposite side, in percentage. Results
Experiment 1
Treatment with 20 mg/kg of BGP-15 for 9 days, perorally
+ probe t related to the control p< 0,05
++ probe t related to the control p<0,06
The treatment reduced the muscle loss caused denervation by 13-38 %.
Experiment 2
Treatment with 60 mg/kg of BGP-15 for 8 days, perorally
+ related to the control p< 0,05
++ related to the control p<0, 1
The treatment reduced the loss of muscle caused by denervation by 28-42 %. The difference is statistically significant at a level of p<0,05 in case of the gastrocnemius and this tendency is clearly seen also in case of soleus and tibial anterior muscles.
Lidocaine-induced immobilization of rat hind limb
Lidocaine induced rat hind limb immobilization was perfomed by the slight modification of the method of L. Soderberg, H. Dyhre, et al. (Anesthesiology 2006; 104:110-21 Ultralong Peripheral Nerve Block by Lidocaine:Prilocaine 1 :1 Mixture in a Lipid Depot Formulation).
Wistar rats weighing around 150-200g were anaesthetised with pentobarbital i.p. The right sciatic nerve was exposed through a 0.5 cm incision and blunt dissection of the gluteal muscles. The sciatic nerve was mobilized carefully and gently, then isolated with a nylon strip. Then μΙ/IOOg bw 80% lidocaine was instilled over the nerve. After 5 min the nylon stripe was removed. A silk suture was used to close the muscle gap. Before tightening the suture 25pl/100g of the 30% solution was instilled on the nerve then the skin was closed. Animals were treated from the day of operation till the seventh day daily orally with BGP-15 (50 mg/kg p.o.) then the musculus gastrocnemius were removed on both sides and weights were measured. The percent mean loss (+ standard error) in the weight of m. gastrocnemius on treated side is shown in the following table.
Treatment Mean change in Number of animals the weight of m.
gastrocnemius in %
+ SE (n)
Control -30.8 + 1.36 8
BGP-15 -16.3 + 4.04* 8
50 mg/kg p.o.
* p < 0.05
The above data confirm that BGP-15 has a high protective effect on the denervation-induced muscle loss.
Thus, our results indicate that the test compound(s) efficiently inhibit both the denervation and the insufficient function (anatomically intact nerve system) induced muscle loss.
Claims
1. Use of an amidoxime derivative of formula I
Ar— A— C— N— RT
I! I
N R2 I I
OR3
wherein
a) Ar represents a pyridyl group,
A is a valence bond,
Ri stands for a hydrogen atom,
R2 represents a hydrogen atom,
R3 stands for a group of formula
OR4
I
— CH2— CH— CH2— R5
wherein R4 represents a hydrogen atom, R5 is a 5-7-membered saturated heterocyclic group containing a nitrogen atom, or b) Ar represents a phenyl group,
A stands for a -CH=CH- group and
bi) Ri is a hydrogen atom,
R2 represents a group of formula
OR4
I
— CH2— CH— CH2— R5 wherein R4 represents a hydrogen atom, R5 stands for a 5-7- membered saturated heterocyclic group containing a nitrogen atom,
R3 is hydrogen atom, or
b2) R2 represents a group of formula OR4
I
— CH^-CH— CHz— R5 wherein R4 represents a hydrogen atom, R5 stands for a 5-7- membered saturated heterocyclic group containing a nitrogen atom,
Ri represents a carbonyl group, R3 is a valence bond between the carbon atom of the carbonyl group and the oxygen atom adjacent to R3,
or a pharmaceutically suitable acid addition salt thereof for the preparation of a pharmaceutical composition for the prevention and/or treatment of muscle atrophy.
2. A use according to claim 1 in which 0-(3-piperidino-2- hydroxy-1-propyl)-nicotinic amidoxime or a pharmaceutically suitable acid addition salt thereof is used as the amidoxime derivative of formula I.
3. A use according to claim 2 in which 0-(3-piperidino-2- hydroxy-1-propyl)-nicotinic amidoxime dihydrochloride of formula II
II
2 HCI
used as the amidoxime derivative of formula.
4. A use according to claim 1 in which hexamethyleneimino-2-hydroxy-propyl)]cinnamic acid amidoxime of formula III III
5. A use according to claim 1 in which 3-styryl-4-(3- hexamethyleneimino-2-hydroxypropyl)-A2-1 ,2,4-oxadiazolin-5- one of formula IV
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| HU1100444A HUP1100444A2 (en) | 2011-08-17 | 2011-08-17 | Pharmaceutical composition |
| HUP1100444 | 2011-08-17 |
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ID=89990395
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3263105A1 (en) | 2016-07-01 | 2018-01-03 | Montana State University | Use of bgp15 to treat familial dysautonomia |
| WO2018225026A1 (en) | 2017-06-08 | 2018-12-13 | N-Gene Research Laboratories, Inc. | Methods for treating nash and for preventing nash-induced hcc |
| WO2020044067A1 (en) | 2018-08-30 | 2020-03-05 | N-Gene Research Laboratories, Inc. | Pharmaceutical combination to modify the effect of beta-receptor blockers and reduce side effects |
Citations (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4187220A (en) | 1977-08-30 | 1980-02-05 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T. | New O-(3-amino-2-hydroxy-propyl)-amidoxime derivatives, process for the preparation thereof and pharmaceutical compositions containing same |
| WO2000007580A2 (en) | 1998-08-03 | 2000-02-17 | N-Gene Kutató Kft. | Pharmaceutical compositions against autoimmune diseases |
| WO2001070674A1 (en) | 2000-03-20 | 2001-09-27 | N-Gene Research Laboratories Inc. | Propenecarboxylic acid amidoxime derivatives, a process for the preparation thereof, and pharmaceutical compositions containing the same |
| US6306878B1 (en) | 1995-09-29 | 2001-10-23 | N-Gene Research Lab Inc | Pharmaceutical compositions containing hydroximic acid derivatives |
| US6440998B1 (en) | 1997-06-23 | 2002-08-27 | N-Gene Research Laboratories, Inc. | Pharmaceutical composition having enhanced antitumor activity and/or reduced side effects, containing an antitumor agent and an hydroximic acid derivative |
| US6451851B1 (en) | 1997-06-23 | 2002-09-17 | N-Gene Research Laboratories Inc. | Pharmaceutical composition with antiviral activity containing an hydroxymic acid derivative and an antiviral agent |
| US6458371B1 (en) | 1995-12-22 | 2002-10-01 | Medgene, Limited | Cosmetic composition and a method for the prevention and/or reduction of the photoaging processes of the skin |
| WO2003007951A1 (en) | 2001-07-17 | 2003-01-30 | N-Gene Research Laboratories Inc. | A synergistic pharmaceutical combination for the prevention or treatment of diabetes |
| US6884424B2 (en) | 1995-12-22 | 2005-04-26 | N-Gene Research Laboratories Inc. | Method for treating the pathological lesions of the skin that develop by ultraviolet radiation of the sunlight |
| WO2005123049A2 (en) | 2004-06-14 | 2005-12-29 | N-Gene Research Laboratories Inc. | A pharmaceutical composition for increasing the mitochondrial genesis |
| WO2005122678A2 (en) | 2004-06-14 | 2005-12-29 | N-Gene Research Laboratories Inc. | A pharmaceutical composition having prokinetic effect and comprising o-(3-piperidino-2-hydroxypropyl) nicotinic amidoxime |
| WO2006079910A2 (en) | 2005-01-28 | 2006-08-03 | N-Gene Research Laboratories Inc. | 0-(3-piperidino-2hydroxypropyl)nicotinic amixodime for treating lesions in the oral cavity |
| WO2009074835A1 (en) | 2007-12-10 | 2009-06-18 | N-Gene Research Laboratories Inc. | Dose reduction of a cannabinoid cb1 receptor antagonist in the treatment of overweight or obesity |
| EP2089032A1 (en) | 2006-11-02 | 2009-08-19 | N-Gene Research Laboratories Inc. | A pharmaceutical composition having antipsychotic, antidepressant or antiepiieptic activity with reduced side effect |
| EP2089031A1 (en) | 2006-11-02 | 2009-08-19 | N-Gene Research Laboratories Inc. | Reduction of overweight or obesity |
-
2011
- 2011-08-17 HU HU1100444A patent/HUP1100444A2/en unknown
-
2012
- 2012-08-14 WO PCT/HU2012/000070 patent/WO2013024311A1/en active Application Filing
Patent Citations (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4187220A (en) | 1977-08-30 | 1980-02-05 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T. | New O-(3-amino-2-hydroxy-propyl)-amidoxime derivatives, process for the preparation thereof and pharmaceutical compositions containing same |
| US6306878B1 (en) | 1995-09-29 | 2001-10-23 | N-Gene Research Lab Inc | Pharmaceutical compositions containing hydroximic acid derivatives |
| US6458371B1 (en) | 1995-12-22 | 2002-10-01 | Medgene, Limited | Cosmetic composition and a method for the prevention and/or reduction of the photoaging processes of the skin |
| US6884424B2 (en) | 1995-12-22 | 2005-04-26 | N-Gene Research Laboratories Inc. | Method for treating the pathological lesions of the skin that develop by ultraviolet radiation of the sunlight |
| US6656955B2 (en) | 1997-06-23 | 2003-12-02 | N-Gene Research Laboratories, Inc. | Pharmaceutical composition having enhanced antitumor activity and/or reduced side effects, containing an antitumor agent and an hydroximic acid derivative |
| US6838469B2 (en) | 1997-06-23 | 2005-01-04 | N-Gene Research Laboratories Inc. | Pharmaceutical composition that exhibits reduced side-effects comprising O-(3-piperidino-2-hydroxy-1-propyl)nicotinic acid amidoxime and a pyrimidine derivative with known antitumor activity |
| US6440998B1 (en) | 1997-06-23 | 2002-08-27 | N-Gene Research Laboratories, Inc. | Pharmaceutical composition having enhanced antitumor activity and/or reduced side effects, containing an antitumor agent and an hydroximic acid derivative |
| US6451851B1 (en) | 1997-06-23 | 2002-09-17 | N-Gene Research Laboratories Inc. | Pharmaceutical composition with antiviral activity containing an hydroxymic acid derivative and an antiviral agent |
| US6720337B2 (en) | 1997-06-23 | 2004-04-13 | N-Gene Research Laboratories, Inc. | Pharmaceutical composition having enhanced antitumor activity and/or reduced side effects, containing an antitumor agent and an hydroxlmic acid derivative |
| WO2000007580A2 (en) | 1998-08-03 | 2000-02-17 | N-Gene Kutató Kft. | Pharmaceutical compositions against autoimmune diseases |
| WO2001070674A1 (en) | 2000-03-20 | 2001-09-27 | N-Gene Research Laboratories Inc. | Propenecarboxylic acid amidoxime derivatives, a process for the preparation thereof, and pharmaceutical compositions containing the same |
| WO2003007951A1 (en) | 2001-07-17 | 2003-01-30 | N-Gene Research Laboratories Inc. | A synergistic pharmaceutical combination for the prevention or treatment of diabetes |
| WO2005123049A2 (en) | 2004-06-14 | 2005-12-29 | N-Gene Research Laboratories Inc. | A pharmaceutical composition for increasing the mitochondrial genesis |
| WO2005122678A2 (en) | 2004-06-14 | 2005-12-29 | N-Gene Research Laboratories Inc. | A pharmaceutical composition having prokinetic effect and comprising o-(3-piperidino-2-hydroxypropyl) nicotinic amidoxime |
| WO2006079910A2 (en) | 2005-01-28 | 2006-08-03 | N-Gene Research Laboratories Inc. | 0-(3-piperidino-2hydroxypropyl)nicotinic amixodime for treating lesions in the oral cavity |
| EP2089032A1 (en) | 2006-11-02 | 2009-08-19 | N-Gene Research Laboratories Inc. | A pharmaceutical composition having antipsychotic, antidepressant or antiepiieptic activity with reduced side effect |
| EP2089031A1 (en) | 2006-11-02 | 2009-08-19 | N-Gene Research Laboratories Inc. | Reduction of overweight or obesity |
| WO2009074835A1 (en) | 2007-12-10 | 2009-06-18 | N-Gene Research Laboratories Inc. | Dose reduction of a cannabinoid cb1 receptor antagonist in the treatment of overweight or obesity |
Non-Patent Citations (29)
| Title |
|---|
| "Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING CO. |
| BODINE, S. C. ET AL., SCIENCE, vol. 294, 2001, pages 1704 - 1708 |
| BODINE, S.C. ET AL.: "Glass DJ.: Signaling pathways perturbing muscle mass", CURR OPIN CLIN NUTR METAB CARE, vol. 13, no. 3, 2010, pages 225 - 9 |
| BODINE, S.C. ET AL.: "Identification of ubiquitin ligases required for skeletal muscle atrophy", SCIENCE, vol. 294, no. 5547, 2001, pages 1704 - 8, XP002386330, DOI: doi:10.1126/science.1065874 |
| BROOKS NAOMI E ET AL: "Effects of resistance exercise combined with essential amino acid supplementation and energy deficit on markers of skeletal muscle atrophy and regeneration during bed rest and active recovery.", MUSCLE & NERVE DEC 2010, vol. 42, no. 6, December 2010 (2010-12-01), pages 927 - 935, XP002687688, ISSN: 1097-4598 * |
| BROWN, W. F.: "A method for estimating the number of motor units in thenar muscles and the changes in motor unit count with ageing", J. NEUROL. NEUROSURG. PSYCHIATRY, vol. 35, 1972, pages 845 - 852 |
| BROWN, W. F.; CHAN, K. M.: "Quantitative methods for estimating the number of motor units in human muscles", MUSCLE NERVE, vol. 5, 1997, pages S70 - S73 |
| CAO PR; KIM HJ; LECKER SH: "Ubiquitin-protein ligases in muscle wasting", INT J BIOCHEM CELL BIOL., vol. 37, no. 10, 2005, pages 2088 - 97 |
| CHEUNG, A. M. ET AL.: "Two-year outcomes, health care use, and costs of survivors of acute respiratory distress syndrome", AM J RESPIR CRIT CARE MED., vol. 174, no. 5, 2006, pages 538 - 44 |
| DELBONO, O., AGING CELL, vol. 2, 2003, pages 21 - 29 |
| DOHERTY, T. J. ET AL., J. APPL. PHYSIOL., vol. 74, 1993, pages 868 - 874 |
| DOYLE, A. ET AL.: "Toll-like receptor 4 mediates lipopolysaccharide-induced muscle catabolism via coordinate activation of ubiquitin-proteasome and autophagy- lysosome pathways", FASEB J., vol. 25, no. 1, 2011, pages 99 - 110, XP055064184, DOI: doi:10.1096/fj.10-164152 |
| FOR THE JAPAN SBMA INTERVENTIONAL TRIAL FOR TAP-144-SR (JASMITT) STUDY ET AL: "Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial", LANCET NEUROLOGY, LANCET PUBLISHING GROUP, LONDON, GB, vol. 9, no. 9, 1 September 2010 (2010-09-01), pages 875 - 884, XP027598917, ISSN: 1474-4422, [retrieved on 20100901], DOI: 10.1016/S1474-4422(10)70182-4 * |
| H. DYHRE ET AL., ANESTHESIOLOGY, vol. 104, 2006, pages 110 - 21 |
| HERRIDGE, M. S. ET AL.: "One-year outcomes in survivors of the acute respiratory distress syndrome", N ENGL J MED., vol. 348, no. 8, 2003, pages 683 - 93 |
| JEFFREY J. BRAULT ET AL., J. BIOL. CHEM., vol. 285, 2010, pages 19460 - 19471 |
| KARAKELIDES, H.; NAIR, K. S., CURR. TOP DEV. BIOL., vol. 68, 2005, pages 123 - 148 |
| LARSSON L., ADV EXP MED BIOL., vol. 642, 2008, pages 92 - 8 |
| LECKER SH; GOLDBERG AL; MITCH WE.: "Protein degradation by the ubiquitin-proteasome pathway in normal and disease states", J AM SOC NEPHROL., vol. 17, no. 7, 2006, pages 1807 - 19 |
| MAMMUCARI, C. ET AL.: "Fox03 controls autophagy in skeletal muscle in vivo", CELL METAB., vol. 6, no. 6, 2007, pages 458 - 71 |
| MEDINA, R.; WING SS.; GOLDBERG AL.: "Increase in levels of polyubiquitin and proteasome mRNA in skeletal muscle during starvation and denervation atrophy", BIOCHEM. J., vol. 308, 1995, pages 631 - 7J |
| MICHAEL J EDDINS ET AL: "Targeting the Ubiquitin E3 Ligase MuRF1 to Inhibit Muscle Atrophy", CELL BIOCHEMISTRY AND BIOPHYSICS, HUMANA PRESS INC, NEW YORK, vol. 60, no. 1 - 2, 30 March 2011 (2011-03-30), pages 113 - 118, XP019902798, ISSN: 1559-0283, DOI: 10.1007/S12013-011-9175-7 * |
| SANDRI, M. ET AL., CELL, vol. 117, 2004, pages 399 - 412 |
| SANDRI, M.: "Autophagy in skeletal muscle.", FEBS LETT., vol. 584, no. 7, 2010, pages 1411 - 6 |
| STITT, T. ET AL., MOL. CELL, vol. 14, 2004, pages 395 - 403 |
| TRENDS MOL MED., vol. 9, no. 8, 2003, pages 344 - 50 |
| VAN MOOK, W. N.; HULSEWÉ-EVERS, R. P.: "Critical illness polyneuropathy", CURR OPIN CRIT CARE., vol. 8, no. 4, 2002, pages 302 - 10 |
| ZHAO, J. ET AL., CELL METAB., vol. 6, 2007, pages 458 - 471 |
| ZHAO, J. ET AL.: "Fox03 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells", CELL METAB., vol. 6, no. 6, 2007, pages 472 - 83 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3263105A1 (en) | 2016-07-01 | 2018-01-03 | Montana State University | Use of bgp15 to treat familial dysautonomia |
| WO2018225026A1 (en) | 2017-06-08 | 2018-12-13 | N-Gene Research Laboratories, Inc. | Methods for treating nash and for preventing nash-induced hcc |
| US11357768B2 (en) | 2017-06-08 | 2022-06-14 | N-Gene Research Laboratories, Inc. | Methods for treating NASH and for preventing NASH-induced HCC |
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