CN109224061B - Application of compound AG120 or pharmaceutically acceptable salt thereof in preparation of drugs for preventing or treating tuberculosis - Google Patents
Application of compound AG120 or pharmaceutically acceptable salt thereof in preparation of drugs for preventing or treating tuberculosis Download PDFInfo
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- CN109224061B CN109224061B CN201811369305.4A CN201811369305A CN109224061B CN 109224061 B CN109224061 B CN 109224061B CN 201811369305 A CN201811369305 A CN 201811369305A CN 109224061 B CN109224061 B CN 109224061B
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- tuberculosis
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to application of a compound AG120 or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating tuberculosis, and a pharmaceutical composition for preventing or treating pulmonary tuberculosis. The compound AG120 can effectively inhibit the infection of tubercle bacillus, thereby providing effective drug support for the prevention or treatment of tuberculosis. Therefore, the invention discloses a compound AG120 which can be used as a lead compound for preventing or treating tuberculosis, has the activity of resisting tubercle bacillus and drug-resistant tubercle bacillus, is particularly suitable for preventing or treating pulmonary tuberculosis, and has wide clinical application prospect and huge market potential.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to application of a compound AG120 or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating tuberculosis, and a pharmaceutical composition for preventing or treating pulmonary tuberculosis.
Background
Tuberculosis (also known as TB) is a disease caused by infection of tubercle bacillus. Tuberculosis often causes pulmonary infections and can also infect other parts of the body; also, most infected patients are asymptomatic, this type of infection is called latent tuberculosis infection, and if appropriate treatment is not given at this time, 10% of the latently infected patients will progress to open tuberculosis, with a mortality rate of about 50%.
It is well known that tuberculosis can occur in any part of the body, but most commonly occurs in the lungs (known as tuberculosis). Extrapulmonary tuberculosis (i.e., tuberculosis occurring in organs other than the lungs) may co-exist with tuberculosis. Also, the general clinical signs and symptoms of tuberculosis include fever, chills, night sweats, loss of appetite, weight loss, and tiredness. In addition, tuberculosis patients may also develop significant clubroot nail symptoms.
Among them, open tuberculosis is most common in the lung (see Lawn, SD; Zumla, AI. Tuberculosis. Lancet.2011-07-02,378(9785): 57-72. and Behera, D. Textbook of Pulmonary medicine2nd. New Delhi: Jaype Brothers Medical publishers.2010:457. in about 90% of cases). Symptoms of tuberculosis may include chest pain and prolonged cough with sputum, while about 25% of people may not exhibit any symptoms; occasionally, the patient may have small amounts of hemoptysis, coughing, and in very rare cases, the infection may also erode the pulmonary artery and the lescent aneurysm, resulting in massive hemorrhage. Further, tuberculosis may develop into a chronic disease and cause large scars on the upper lung lobes. Clinical studies have shown that the upper lobe is more susceptible to tuberculosis than the lower lobe, but the reason for this difference is not known at present; a possible explanation is that the upper lung lobes are better ventilated or have a poorer lymphatic drainage capacity.
Furthermore, in 15% to 20% of cases of open tuberculosis, tubercle bacillus infection can spread outside the lungs, causing other kinds of tuberculosis, and these conditions are classified as "extrapulmonary tuberculosis" (Golden MP, Vikram hr. extrapulmony tuberculosis: an overview. american Family physicians.2005, 72(9): 1761-8). Extrapulmonary tuberculosis is common in individuals or young children with immunosuppression, and more than 50% of HIV virus carriers with tuberculosis have extrapulmonary tuberculosis.
It has been reported (Erica Hansen, et al, blood.2014,124: 3734; Maeve air lower, et al, Phase I study of AG-120, an IDH1mutant enzyme inhibitor: Results from the expression of the fungal enzyme catalysis and expansion countries, Journal of Clinical Oncology) that compound AG120 (or AG-120) is capable of effectively inhibiting mutant IDH enzyme activity intracellularly, thereby effectively reducing intracellular 2-HG levels and inhibiting growth factor-independent cell proliferation and restoring erythropoietin-induced cell differentiation in-TF 1IDH1-R132H cells.
Mutations in the IDH gene occur in 28% of intrahepatic cholangiocarcinomas, as well as in other types of biliary systems. Recent research results show that AG120 as a new drug targeting IDH mutation achieves good curative effect in phase I clinical tests, part of tumors of patients are obviously reduced, part of tumors are not reduced, and half-year progression-free survival rate is 40%. Currently, AG120 is actively in progress in a three-phase clinical trial (ClarIDHy study) for IDH-mutated biliary tumors.
In addition, the medicine (compound AG120) has remarkable curative effect in IDH mutation refractory and acute myeloid leukemia, the probability of complete tumor disappearance after the medicine is taken is as high as 30 percent, and the effective rate is as high as 42 percent; therefore, the drug has been filed for marketing to the FDA in the united states. Therefore, the prior art shows that the compound AG120 provides a good treatment scheme for patients with part of IDH mutated and non-drug-curable biliary tract system tumors.
Therefore, the compound AG120 is not reported to be used as an anti-tubercle bacillus drug in the existing medical papers and works.
Disclosure of Invention
The inventors of the present invention unexpectedly found that compound AG120 is effective in inhibiting the in vivo survival rate of tubercle bacillus; on this basis, the invention aims to provide a lead compound AG120 which can be used as an anti-tubercle bacillus medicament.
Therefore, in a first aspect, the present invention provides a use of compound AG120 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating tuberculosis, wherein the structural formula of the compound AG120 is:
in a preferred embodiment of the invention, the tuberculosis in the above-mentioned use is tuberculosis or extrapulmonary tuberculosis.
In a further preferred embodiment of the invention, the extrapulmonary tuberculosis in the above-mentioned use is selected from any one of the following: renal tuberculosis, intestinal tuberculosis, osteoarticular tuberculosis, tuberculous meningitis, tuberculous peritonitis, and epididymal tuberculosis.
In addition, the second aspect of the present invention also provides a pharmaceutical composition for preventing or treating tuberculosis, which comprises an effective amount of compound AG120 and a pharmaceutically acceptable carrier; wherein the structural formula of the compound AG120 is:
among them, the compound AG120 of the present invention can be obtained by chemical synthesis or purchased directly from Selleck corporation.
Preferably, in the above pharmaceutical composition for preventing or treating tuberculosis, the pharmaceutically acceptable carrier is selected from any one or more of the following: fillers, binders, solubilizers, disintegrants, and glidants.
Wherein the fillers include, but are not limited to: lactose, microcrystalline cellulose, starch, dextrin, fructose, sucrose, mannitol, sorbitol, xylitol, maltitol, or a combination thereof. Wherein the adhesive includes, but is not limited to: polyvinylpyrrolidone, hypromellose, carboxymethylcellulose (sodium), hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin, gum arabic, guar gum, xanthan gum, dextrin, starch, or a combination thereof. Wherein the solubilizing agents include, but are not limited to: sodium lauryl sulfate, poloxamer, beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, hydroxyethyl beta-cyclodextrin, alpha-cyclodextrin, polysorbate, polyethylene glycol, polyvinylpyrrolidone, or a combination thereof. Wherein, the disintegrant includes but is not limited to: crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropylcellulose, microcrystalline cellulose, or a combination thereof. Wherein the glidant includes, but is not limited to: magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, polyethylene glycol, sodium stearyl fumarate, or combinations thereof.
Preferably, the dosage form of the pharmaceutical composition for preventing or treating pulmonary tuberculosis is selected from any one of the following: tablet, capsule, pill, granule, suspension, oral liquid, transdermal preparation, spray, powder for injection and water injection.
In order to avoid the first-pass effect, it is further preferred that the above pharmaceutical composition for preventing or treating tuberculosis is in a dosage form selected from any one of the following: transdermal preparation, spray, powder for injection and water injection.
The inventor proves that the compound AG120 can obviously inhibit the intracellular survival of tubercle bacillus infected macrophages through a series of experiments. Meanwhile, relevant animal experiment results prove that after the mice are infected by the tubercle bacillus for one week, the compound AG120 with the dose of 2 mg/kg/day is given, and after the tubercle bacillus is continuously orally taken for three weeks, pathological damage of the lungs of the mice is obviously relieved, and the amount of the bacteria loaded in the lungs is obviously reduced.
In conclusion, the technical scheme provided by the invention clearly describes the new application of the compound AG120 or the pharmaceutically acceptable salt thereof in preparing the drugs for preventing or treating tuberculosis, and the compound AG120 can effectively inhibit the infection of tubercle bacillus, thereby providing effective drug support for preventing or treating tuberculosis.
Therefore, the invention discloses a compound AG120 which can be used as a lead compound for preventing or treating tuberculosis, has the activity of resisting tubercle bacillus and drug-resistant tubercle bacillus, is particularly suitable for preventing or treating pulmonary tuberculosis, and has wide clinical application prospect and huge market potential.
Drawings
FIG. 1 is a graph of intracellular CFU after 2 hours and 24 hours of infection of mouse macrophages with Mycobacterium tuberculosis;
FIG. 2 is a graph showing the results of hematoxylin-eosin staining (H & E) performed on mouse lung sections;
FIG. 3 is a statistical chart of the bacterial load of M.tuberculosis in mice.
Detailed Description
The present invention will be further described with reference to specific embodiments, but the present invention is not limited to the following embodiments. The experimental procedures in the following examples, unless otherwise specified, were carried out in a conventional manner; materials, reagents and the like used in the following examples are commercially available from public unless otherwise specified.
Example 1
C57BL/6 mice and DB/DB mice Db/Db (leptin receptor (Lepr) mutant) peritoneal primary macrophages with 1 × 105One/well was seeded in 48-well cell culture plates, and after about 2h for cells to adhere, the complete medium 1640 was removed and fresh complete medium was added for overnight culture. The following day, 1H before infection was replaced with fresh 1640 containing 10% serum without double antibody and infected with tubercle bacillus (H37Rv) at a MOI of 5. After 2-3h of infection, the supernatant was discarded, followed by culturing the cells in amikacin containing medium for 2h, discarding the supernatant and replacing with 1640 containing 10% serum without diabody and continuing at 37 ℃ with 5% CO2Cells were cultured in an incubator for 24 h. And (3) discarding the supernatant, washing the cells with PBS, then lysing the cells with PBS containing 1% triton-100, taking cell lysate, smearing the cell lysate on a MiddleBook 7H10 agar culture plate containing amphotericin B, placing the cell lysate in an incubator at 37 ℃ for 2-3 weeks, and finally completing colony counting.
The results of the counts are shown in FIG. 1, which shows intracellular CFU of WT and DB/DB mouse macrophages and macrophages after treatment with Compound AG120 after 2 hours and 24 hours of tubercle bacillus infection; moreover, the experimental result shows that the compound AG120 can inhibit the intracellular survival of tubercle bacillus infected Db/Db mouse macrophage.
Example 2
C57BL/6 mice were divided into two groups and Db/Db mice were divided into two groups of 6 mice each, each of which was administered with tubercle bacillus rhinofectus (H37Rv) at a dose of 200 CFU/mouse 1 week after infection for 3 weeks at a dose of 2 mg/kg/day (compound AG120) continuously orally with pure water as a blank. The mice were sacrificed by cervical dislocation, one leaf of the lung was removed, fixed with 4% paraformaldehyde, and after paraffin sectioning, H & E staining was performed to observe the pathological injury condition of the lung.
The experimental result is shown in figure 2, and the pathological damage of the lung of the mice treated by the compound AG120 is obviously reduced; therefore, the experimental results of this example show that the compound AG120 is effective in alleviating pathological damages of the mouse lung.
Example 3
One week after infection and 3 weeks after administration of the mouse lung tissue of example 2 above was divided into three portions, and the three portions were treated by grinding with 1ml of 1% triton-100-containing PBS, and diluted in a gradient manner to obtain 10 portions-3、10-4100ml of the tissue suspension is uniformly coated on a MiddleBook 7H10 agar culture plate containing amphotericin B, and then the tissue suspension is placed in an incubator at 37 ℃ for 2-3 weeks to complete colony counting, and the specific result is shown in figure 3.
The experimental results of this example demonstrate that the compound AG120 significantly reduces the bacterial load of mycobacterium tuberculosis in mice.
Comprehensive analysis of the above examples shows that the compound AG120 can effectively inhibit the in vivo survival rate of tubercle bacillus, thereby providing effective drug support for the treatment of tuberculosis.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.
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| CN107428690A (en) * | 2014-12-22 | 2017-12-01 | 美国政府健康及人类服务部 | Mutation IDH1 inhibitor available for treating cancer |
| CN108697698A (en) * | 2015-10-15 | 2018-10-23 | 阿吉奥斯制药公司 | Combination treatment for treating malignant tumour |
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| CN107428690A (en) * | 2014-12-22 | 2017-12-01 | 美国政府健康及人类服务部 | Mutation IDH1 inhibitor available for treating cancer |
| CN108697698A (en) * | 2015-10-15 | 2018-10-23 | 阿吉奥斯制药公司 | Combination treatment for treating malignant tumour |
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