Application of compound palosuran in prevention and treatment of diseases such as skeletal muscle atrophy
阅读说明：本技术 化合物palosuran防治骨骼肌萎缩等疾病的用途 (Application of compound palosuran in prevention and treatment of diseases such as skeletal muscle atrophy ) 是由 杜冠华 杨秀颖 陈熙 强桂芬 殷琳 贾伟华 王诺琪 张莉 侯碧玉 于 2018-07-27 设计创作，主要内容包括：本发明涉及生物医疗领域,具体涉及一种化合物palosuran(CAS No.:540769-28-6)在制备预防、缓解和/或治疗骨骼肌萎缩、肌病及肌肉骨骼并发症的药物中的用途。本发明涉及的化合物,具有显著提高骨骼肌力量、提高骨骼肌纤维束横截面积、改善骨骼肌分泌功能的作用。该化合物作用新颖,容易合成,用量较低,具有很好的应用和开发前景。(The invention relates to the field of biological medicine, in particular to application of a compound palosuran (CAS No. 540769-28-6) in preparing a medicine for preventing, relieving and/or treating skeletal muscle atrophy, myopathy and musculoskeletal complications. The compound has the effects of obviously improving the strength of skeletal muscle, improving the cross section area of a skeletal muscle fiber bundle and improving the secretion function of the skeletal muscle. The compound has novel effect, easy synthesis and low dosage, and has good application and development prospects.)
1. The application of the compound shown as the formula (I) in preparing products for preventing, relieving and/or treating skeletal muscle atrophy, myopathy and musculoskeletal complications,
2. the use of claim 1, wherein said skeletal muscle atrophy, myopathy or musculoskeletal complications comprise genetic disorders, neurological disorders, muscular dystrophy, obesity, metabolic syndrome, diabetes and related disorders resulting in skeletal muscle atrophy, myopathy or musculoskeletal complications.
3. The use according to claim 2, wherein the obesity is a chronic metabolic disease caused by various factors, characterized by an abnormally increased percentage of body fat to body weight due to an increase in the volume of fat cells and the number of cells in the body and an excessive deposition of fat locally.
4. Use according to claim 2, characterized in that the metabolic syndrome is characterized by abnormal fat metabolism, obesity and insulin resistance.
5. The use according to claim 2, wherein said diabetes mellitus comprises type 1 and type 2 diabetes mellitus.
6. The use according to claim 2, wherein said diabetes-related disorders comprise diabetic hyperglycemia, diabetic vasculopathy, diabetic nephropathy, diabetic peripheral circulation dysfunction, diabetic peripheral neuropathy, diabetes mellitus complicated with hyperlipidemia.
7. The use of claim 1, wherein said skeletal muscle atrophy, myopathy or musculoskeletal complications comprise a decrease in skeletal muscle mass, a decrease in skeletal muscle strength or skeletal muscle secretory function resulting from genetics, malnutrition, obesity, metabolic syndrome, diabetes and related conditions.
8. Use of a pharmaceutical composition for the manufacture of a medicament for the treatment and/or prevention of skeletal muscle atrophy, myopathy, and musculoskeletal complications, wherein the pharmaceutical composition comprises an effective amount of a compound according to (1) and a pharmaceutically acceptable carrier;
9. the use according to claim 8, wherein said pharmaceutical composition comprises the following dosage forms: solutions, suspensions, lyophilized powders, emulsions, pills, capsules, powders, controlled release, sustained release formulations and microsomal delivery systems.
10. The use according to claim 8, wherein said pharmaceutically acceptable carrier comprises starch, dextrin, sodium carboxymethylcellulose, magnesium stearate, talc.
11. The use according to claim 8, wherein the compound is administered in a daily dose in the range of 0.01 to 1000mg/kg body weight.
12. Use according to any one of claims 1 to 11, wherein said product comprises a pharmaceutical or nutraceutical product.
Technical Field
The invention relates to the field of biological medicines, in particular to application of a compound palosuran in preparation of medicines for preventing, relieving and/or treating skeletal muscle atrophy, myopathy and musculoskeletal complications caused by heredity, malnutrition, obesity, metabolic syndrome, diabetes and related diseases.
Background
Clinically, the reduction in skeletal muscle volume compared to the previous state of the muscles of the same or self-aged person, leading to macroscopic or imagewise recognizable local or extensive muscle volume reduction, or microscopic observation of decreased number or diameter of muscle fibers, is defined as muscular atrophy [ e.g., luohan, yuanyun, diagnosis of muscular atrophy and differential diagnosis [ J ]. journal of practical internal medicine, 2009, (02):97-100 ]. Muscle fiber diameters < 35 μm for adult males and < 28 μm for adult females are diagnostic of skeletal muscle atrophy. Skeletal muscle atrophy, myopathy and musculoskeletal complications may be caused by a variety of causes including genetics, malnutrition, exercise deficiency, disease, and the like. The current methods for treating skeletal muscle atrophy, myopathy and musculoskeletal complications mainly comprise: clenbuterol hydrochloride, choline chloride, growth factors and other western medicines, traditional Chinese medicines, electrical stimulation and other physical therapies, gene therapy and the like [ promising longevity, skeletal muscle atrophy prevention and treatment research progress [ J ] Chinese medicine guide, 2017, (09):34-37 ]. However, the current treatment status about skeletal muscle atrophy is: poor compliance and poor yield of physical therapy methods; the variety of the treatment medicines is less, and medicines with good treatment effect are lacked; gene therapy lacks extensive clinical trial validation. Therefore, the current treatment situation of skeletal muscle atrophy, myopathy and musculoskeletal complications is very severe.
In recent years, skeletal muscle atrophy caused by metabolic diseases has been receiving attention. It has been found that obesity and diabetes can also cause skeletal muscle atrophy. And as skeletal muscle is an important tissue of energy metabolism, skeletal muscle atrophy can also in turn aggravate glycolipid metabolic disorders of obesity and diabetes [ Wang, Weekover.2 type diabetes and muscular atrophy research progress [ J ]. China journal of sports medicine, 2017, (07): 645-. Obesity is a disease in which an intake of energy is greater than a consumption thereof, resulting in excessive fat deposition, resulting in weight gain. In an obese state, excessive storage of body fat enhances fat breakdown, thereby producing large amounts of free fatty acids [ Niguhua, ZJING, Zhengfeng field, the present and trend of obesity epidemics in China [ J ] Chinese food and nutrition, 2013, (10):70-74 ]. The increase of free fatty acids in blood severely inhibits the sensitivity of skeletal muscle to insulin, resulting in impaired glucose utilization. Therefore, in the obese state, glycolipid metabolic disorders can cause progressive loss of skeletal muscle weight and function. Furthermore, obesity can also cause alterations in various signal-regulatory pathways associated with skeletal muscle production, degradation, and thus skeletal muscle atrophy, such as: excessive intramuscular fat deposition up-regulates autophagy in skeletal muscle, leading to increased protein degradation and skeletal muscle atrophy; under the obesity state, the skeletal muscle insulin signal pathway is inhibited, so that the PKB-mTOR signal pathway can be indirectly inhibited, and the protein synthesis is reduced; the research on the molecular mechanism of obese muscular atrophy induced by obesity to decrease leptin and further decrease muscle protein synthesis [ Rolin, Yanjinpeng, Wang Song, Liaoxin, Jenwei ] advances [ J ] Chinese rehabilitation theory and practice, 2017, (05):553-557 ].
In the obesity state, if the glycolipid metabolic disorder and chronic inflammation are further aggravated, the diabetes mellitus can be developed into
The current drugs for treating the obesity mainly comprise central appetite suppressants, lipase inhibitors for reducing fat absorption, drugs for promoting fat tissue decomposition and the like, but the current drugs for treating the obesity mainly comprise central appetite suppressants, thiazolidine inhibitors for promoting fat absorption, drugs for promoting fat tissue decomposition and the like, but the current drugs for treating the obese skeletal muscle atrophy are not specific drugs for improving the diabetic skeletal muscle atrophy, but the current drugs for treating the diabetic atrophy are fewer in types, mainly comprise growth factors or hormones.
In conclusion, it is of great practical significance to develop a medicament for preventing, alleviating and/or treating skeletal muscle atrophy, myopathy and musculoskeletal complications.
The compound palosuran provided by the invention is an antagonist of
Disclosure of Invention
The invention aims to solve the technical problem of providing the application of a compound palosuran in preparing products for preventing, relieving and/or treating skeletal muscle atrophy, myopathy and musculoskeletal complications.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical proposal of the invention provides the application of the compound shown as the formula (I) in preparing products for preventing, relieving and/or treating skeletal muscle atrophy, myopathy and musculoskeletal complications,
the skeletal muscle atrophy, myopathy and musculoskeletal complications comprise genetic disorders, neurological dysfunction, muscular dystrophy, obesity, metabolic syndrome, diabetes and skeletal muscle atrophy, myopathy and musculoskeletal complications caused by the diseases.
The skeletal muscle atrophy, myopathy and musculoskeletal complications comprise heredity, neurological dysfunction, muscular dystrophy, obesity, metabolic syndrome, reduction of skeletal muscle weight, reduction of skeletal muscle strength and skeletal muscle secretion function caused by diabetes and related diseases, and the like.
The obesity refers to a chronic metabolic disease caused by various factors and is characterized in that the volume and the cell number of fat cells in a body are increased, so that the percentage of body fat to the body weight is abnormally increased, and fat is excessively deposited locally. The metabolic syndrome is characterized by abnormal fat metabolism, obesity and insulin resistance. The diabetes mellitus comprises type 1 diabetes mellitus and
The product comprises medicines and health-care products.
A male C57BL/J mouse and a male KKAy mouse with spontaneous diabetes induced by high-fat diet are adopted to establish an obesity and diabetes animal model. The effect of the compound on the autonomic activity, skeletal muscle strength, sensory/motor nerve function, skeletal muscle cross-sectional area microstructure and skeletal muscle factor of animals is tested. Determining the application of the compound in preparing products for preventing, relieving and/or treating skeletal muscle atrophy, myopathy and musculoskeletal complications.
The invention is characterized in that the compound can achieve the treatment and prevention effects by being taken in small amount. The medicine is safe and reliable.
The invention aims to provide a compound represented by the general formula: (I) novel use of the compounds shown. The application in preparing products for preventing, relieving and/or treating skeletal muscle atrophy, myopathy and musculoskeletal complications.
A compound of formula (I) having the trade name palosuran, also known as ACT-058362, and the molecular formula C25H30N4O2The chemical name is 1- [2- (4-benzyl-4-hydroxy-piperidin-1-yl) -ethyl]-3- (2-methyl-quinolin-4-yl) -urea sulfate, CAS number 540769-28-6, is a high affinity antagonist of the human urotensin receptor. Clozel M et al [ Pharmacology of the urotensin-II receptor antadonostist palosuran (ACT-058362;
1- [2- (4-benzyl-4-hydroxy-piperidine-1-yl) -ethyl ] -3- (2-methyl-quinolin-4-yl) -urea sulfate first optimization of a pathological role in the urinary System [ J ] Journal of Pharmacology and Experimental therapeutics,2004, 311(1):204-212 ] was found to have the effect of preventing the subsequent development of acute renal failure and ischemia without lowering blood pressure, and can be used as a selective renal vasodilator. Developed by the company Actelion, the compound was orally active and well tolerated in a phase 1 clinical trial for 23 patients with metastatic melanoma and in a phase 1 clinical trial for one patient with diabetes. In 2007, the compound terminated
The second aspect of the technical scheme of the invention provides an application of a pharmaceutical composition in preparing a medicament for treating and/or preventing skeletal muscle atrophy, myopathy and musculoskeletal complications, wherein the pharmaceutical composition comprises an effective dose of the compound as shown in (I) and a pharmaceutically acceptable carrier;
the pharmaceutical composition comprises the following dosage forms: solutions, suspensions, lyophilized powders, emulsions, pills, capsules, powders, controlled release, sustained release formulations and microsomal delivery systems.
The pharmaceutically acceptable carrier comprises starch, dextrin, sodium carboxymethylcellulose, magnesium stearate and talcum powder.
The daily dosage of the compound is within the range of 0.01-1000mg/kg body weight.
The invention relates to a pharmaceutical composition shown in a general formula (I), which comprises an effective amount of a compound shown in the general formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.
The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable daily dosage range for a compound of the invention is from 0.01 to 1000mg/kg body weight, preferably from 0.1 to 100mg/kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means. The compounds or compositions of the present invention may be used alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage forms by parenteral routes such as intravenous, intramuscular, subcutaneous, nasal, oral, mucosal, ocular, pulmonary and respiratory, dermal, rectal and the like. The dosage form for administration is a liquid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
Advantageous technical effects
1. The compounds of the invention can prevent, alleviate and/or treat skeletal muscle atrophy, myopathy and musculoskeletal complications. The use of the compounds of the invention for the prevention, alleviation and/or treatment of skeletal muscle atrophy, myopathy and musculoskeletal complications is disclosed for the first time. Especially, no obvious effective medicine exists in clinic for the diseases. The compound widens the selection field of medicines for resisting skeletal muscle atrophy, myopathy and musculoskeletal complications.
2. At present, no patent and literature report on palosuran in skeletal muscle atrophy, myopathy and musculoskeletal complications exists internationally. The patent reports for the first time that the compound has the effects on skeletal muscle atrophy, myopathy and musculoskeletal complications.
3. The application of the compound in the invention proves that the compound has the effects of obviously improving the strength of skeletal muscle, improving the cross section area of a skeletal muscle fiber bundle and improving the secretion function of the skeletal muscle. The compound is developed as a medicament and has obvious advantages.
4. The compound of the invention can achieve the treatment and prevention effects by being taken in a small amount. The medicine is safe and reliable. The compound is developed as a medicament and has obvious advantages.
Drawings
Defining: palosuran is a compound of the invention
FIG. 1 shows that the compound has no obvious influence on the general conditions of high fat induced obesity C57BL/6J mice, and the like, has no obvious influence on blood sugar and blood fat metabolism, and can obviously improve the expression levels of muscle factor leukemia inhibitory factor, brain-derived neurotrophic factor, complement C1 q/tumor necrosis factor-related protein 15 and type III fibronectin module-containing protein 5 for promoting skeletal muscle growth in gastrocnemius. The compound group was administered with palosuran by intraperitoneal injection for 21 days, and the control group and the model group were administered with physiological saline by intraperitoneal injection. P <0.05 x, P <0.005 compared to model group.
FIG. 2 shows that the compound can increase the expression level of inflammatory factors in gastrocnemius of high fat induced obesity C57BL/6J mice, and interleukin 6 and
FIG. 3 shows that the compound does not increase the expression level of skeletal muscle inhibitor and interleukin 7 for inhibiting muscle growth in gastrocnemius of C57BL/6J mice with high fat induction obesity. The compound group was administered with palosuran by intraperitoneal injection for 21 days, and the control group and the model group were administered with physiological saline by intraperitoneal injection.
Figure 4. the compounds can significantly improve the forelimb tension in
Figure 5. the compounds can significantly improve the iron wire hang time of
Figure 6. the compound can significantly reduce daytime autonomic activity in
Figure 7. the compounds significantly increased the soleus muscle (slow muscle) fiber bundle cross-sectional area in
Figure 8. the compound significantly increased the tibialis anterior (fast muscle) muscle fiber bundle cross-sectional area in
Figure 9. compound had no effect on sensory nerve function in spontaneously type 2 diabetic KKAy mice, i.e. on thermal and mechanical pain thresholds. The compound group was administered with palosuran by intraperitoneal injection for 32 days, and the control group and the model group were administered with physiological saline by intraperitoneal injection.
Figure 10. compound had no effect on motor function, i.e. on the speed of transmission of the sciatic nerve, in spontaneously type 2 diabetic KKAy mice. The compound group was administered with palosuran by intraperitoneal injection for 32 days, and the control group and the model group were administered with physiological saline by intraperitoneal injection.
FIG. 11. the compound can significantly increase the expression level of neurotrophic factors and their transcription factors, peroxisome proliferator-activated receptor y coactivator 1 α in soleus muscle of spontaneously type 2 diabetic KKAY mice the compound group was administered by intraperitoneal injection of palosuran at 10mg/kg for 32 days, and the control group and the model group were administered by intraperitoneal injection of normal saline, P <0.05 and P <0.01 compared with the model group.
FIG. 12 shows that the compound can significantly improve the expression level of fibronectin type III protein 5 and complement C1 q/TNF-related protein 15 in tibialis anterior muscle of KKAy mice with
Detailed Description
The following further describes the effect of the compounds of formula (I) in the preparation of a medicament for the prevention, alleviation and/or treatment of skeletal muscle atrophy, myopathy and musculoskeletal complications, in combination with the present invention.
The following examples illustrate the invention in more detail and are not intended to limit the invention in any way. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
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