阅读说明：本技术 坎地沙坦酯或其药学上可接受的盐在制备预防和/或治疗新型冠状病毒肺炎药物中的应用 (Application of candesartan cilexetil or pharmaceutically acceptable salt thereof in preparation of medicine for preventing and/or treating novel coronavirus pneumonia ) 是由 罗海彬 王鑫 李哲 黄仪有 周倩 于 2020-03-10 设计创作，主要内容包括：本发明公开了坎地沙坦酯或其药学上可接受的盐在制备预防和/或治疗新型冠状病毒肺炎药物中的应用。本发明所述坎地沙坦酯、其水解产物坎地沙坦均与引发肺部等炎症的新型冠状病毒靶点3CL水解酶(Mpro)具有较强结合强度,可显著性地抑制3CL水解酶活性,其中坎地沙坦酯、其水解产物坎地沙坦对3CL水解酶(Mpro)的IC<Sub>50</Sub>分别为2.78±0.31μM、9.45±0.73μM,表明所述坎地沙坦酯和其水解产物坎地沙坦具有防治新型冠状病毒引发肺炎的作用,可制备为抗肺炎药物进行应用。(The candesartan cilexetil and the candesartan hydrolysate thereof have stronger bonding strength with a novel coronavirus target 3C L hydrolase (Mpro) which causes inflammation of lung and the like, and can obviously inhibit the activity of 3C L hydrolase, wherein the candesartan cilexetil and the candesartan hydrolysate thereof have IC (integrated Circuit) of the 3C L hydrolase (Mpro) 50 Respectively 2.78 +/-0.31 mu M and 9.45 +/-0.73 mu M, which shows that the candesartan cilexetil and the candesartan hydrolysate thereof have the effect of preventing and treating pneumonia caused by novel coronavirus, and can be prepared into an anti-pneumonia medicament for application.)

1. The application of candesartan cilexetil or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing any one of the candesartan cilexetil and the pharmaceutically acceptable salt thereof in preparing a medicine for preventing and/or treating 2019 novel coronavirus inflammation.

2. The application of candesartan or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating 2019 novel coronavirus inflammation.

3. The use according to claim 1 or 2, characterized in that candesartan cilexetil or a pharmaceutically acceptable salt thereof, candesartan cilexetil or a pharmaceutically acceptable salt thereof inhibits coronavirus 3C L hydrolase activity.

4. Use according to claim 1 or 2, characterized in that the preventive and/or curative 2019 of a novel coronavirus inflammation drug is suitable for use in humans or animals.

5. Use of candesartan cilexetil or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a coronavirus 3C L hydrolase inhibitor.

6. Use of candesartan or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a coronavirus 3C L hydrolase inhibitor.

7. A medicament for the prevention and/or treatment of a novel type of coronavirus inflammation, comprising one or more of candesartan cilexetil, a pharmaceutically acceptable salt of candesartan cilexetil, candesartan or a pharmaceutically acceptable salt of candesartan.

8. A coronavirus 3C L hydrolase inhibitor medicament, comprising one or more of candesartan cilexetil, a pharmaceutically acceptable salt of candesartan cilexetil, candesartan or a pharmaceutically acceptable salt of candesartan.

9. The medicament of claim 7 or 8, wherein the medicament is a capsule, a tablet, a pill, a granule, an injection or a spray.

10. Medicament according to claim 7 or 8, characterized in that it is suitable for use in humans or animals.

Technical Field

The invention relates to the technical field of pharmacy and pulmonary diseases, in particular to application of candesartan cilexetil or pharmaceutically acceptable salt thereof in preparing a medicine for preventing and/or treating novel coronavirus inflammation.

Background

The novel coronavirus pneumonia (COVID-19) is pneumonia caused by infection of a novel coronavirus (SARS-CoV-2), and is clinically characterized by fever, dry cough, hypodynamia, and gradually progressing to symptoms of asthma, hypodynamia and the like. Although some mild patients may heal themselves, more patients progress rapidly in the later stages, developing Acute Respiratory Distress Syndrome (ARDS), sepsis, renal failure, refractory metabolic acid poisoning, and bleeding coagulopathy. The disease is mainly transmitted and contacted by respiratory droplets, is generally susceptible to crowds and has high infectivity.

The novel coronavirus pneumonia has no specific treatment medicine, and currently, antiviral medicine treatment and symptomatic treatment are mostly adopted for treatment, but the two treatments still cannot meet the clinical requirements. On the one hand, antiviral drugs such as ribavirin are easy to cause side effects such as diarrhea, arrhythmia, abnormal liver function and the like, and especially, the antiviral drugs are carefully used for the old with various basic diseases such as hypertension and diabetes. On the other hand, symptomatic treatment cannot effectively reverse the disease progress of severe patients, and part of patients have poor effect after antiviral and anti-inflammatory treatment, and are easy to be infected together to cause multiple and diffuse lesions. Therefore, it is of great significance to develop targeted drug research against novel coronaviruses.

The novel coronavirus belongs to the β coronavirus genus, and the key hydrolase 3C L (Mpro) for controlling RNA replication is a key target for developing a novel coronavirus targeted drug, the 3C L hydrolase can hydrolyze to generate non-structural proteins (NSPs) for virus replication, such as RNA-dependent RNA polymerase and helicase, after the activity of the 3C L hydrolase is inhibited, the transcription and replication of the virus are affected, and therefore, the propagation and diffusion of the virus are inhibited, and the 3C L hydrolase is a good drug target for resisting coronavirus infection.

The candesartan cilexetil is a prodrug of candesartan, is mainly used for treating essential hypertension, can be absorbed in gastrointestinal tracts, and is quickly converted into an active substance candesartan, the candesartan reaches a peak in blood plasma after being taken for 3-4 hours, is mainly distributed at the periphery, and rarely penetrates through a blood brain barrier.

Disclosure of Invention

The invention provides application of candesartan cilexetil or pharmaceutically acceptable salts thereof in preparation of a medicine for preventing and/or treating novel coronavirus inflammation, aiming at the problem that relevant inflammatory diseases of lung and the like caused by novel coronavirus lack of effective prevention and treatment medicines at present, and predicts the binding mode of candesartan cilexetil and hydrolysate thereof with a target (Mrpo) of novel coronavirus 3C L by methods of molecular docking, absolute free energy perturbation and the like, and verifies the inhibitory activity of candesartan cilexetil and hydrolysate thereof on 3C L hydrolase through an enzyme activity test, so that the candesartan cilexetil and hydrolysate thereof can be combined with the target of the novel coronavirus 3C L hydrolase to inhibit the activity of 3C L hydrolase and inhibit the production of non-structural functional protein, thereby preventing the transcription and replication of viruses, and indicating that the candesartan cilexetil and hydrolysate thereof have the effect of preventing and/or treating novel coronavirus inflammation, and can be prepared into a medicine for preventing and/or treating novel coronavirus inflammation for application.

The second purpose of the invention is to provide application of candesartan or a pharmaceutically acceptable salt thereof in preparing a medicine for preventing and/or treating 2019 novel coronavirus inflammation.

The third purpose of the invention is to provide the application of candesartan cilexetil or pharmaceutically acceptable salt thereof in preparing a coronavirus 3C L hydrolase inhibitor medicament.

The fourth purpose of the invention is to provide the application of candesartan or pharmaceutically acceptable salt thereof in preparing a coronavirus 3C L hydrolase (Mpro) inhibitor medicament.

A fifth object of the present invention is to provide a medicament for the prevention and/or treatment of a novel type of coronavirus inflammation comprising one or more of candesartan cilexetil, a pharmaceutically acceptable salt of candesartan cilexetil, candesartan or a pharmaceutically acceptable salt of candesartan.

A sixth object of the present invention is to provide a medicament of an inhibitor of the coronavirus 3C L hydrolase (Mpro) comprising one or more of candesartan cilexetil, a pharmaceutically acceptable salt of candesartan cilexetil, candesartan or a pharmaceutically acceptable salt of candesartan.

The above object of the invention is achieved by the following scheme:

the application of candesartan cilexetil or pharmaceutically acceptable salt thereof or a pharmaceutical composition containing any one of the candesartan cilexetil and the pharmaceutically acceptable salt thereof in preparing a medicine for preventing and/or treating 2019 novel coronavirus inflammation.

The candesartan cilexetil has the structure of formula (I):

further, the candesartan cilexetil or the pharmaceutically acceptable salt thereof may have strong binding strength with coronavirus 3C L hydrolase (Mpro).

Further, the candesartan cilexetil or pharmaceutically acceptable salt thereof inhibits coronavirus 3C L hydrolase (Mpro) activity.

Further, the novel medicament for preventing and/or treating 2019 coronavirus inflammation is suitable for human or animals.

Further, the animals include but are not limited to pets such as cats, dogs, parrots, fish or octopus.

The invention also protects the application of candesartan or pharmaceutically acceptable salts thereof in preparing medicaments for preventing and/or treating 2019 novel coronavirus inflammation.

The candesartan cilexetil has the structure of formula (II):

further, the candesartan or a pharmaceutically acceptable salt thereof may have strong binding strength with coronavirus 3C L hydrolase.

Further, the candesartan or a pharmaceutically acceptable salt thereof inhibits coronavirus 3C L hydrolase activity.

Further, the novel medicament for preventing and/or treating 2019 coronavirus inflammation is suitable for human or animals.

Further, the animals include but are not limited to pets such as cats, dogs, parrots, fish or octopus.

The invention also protects the application of candesartan cilexetil or pharmaceutically acceptable salt thereof in preparing a coronavirus 3C L hydrolase (Mpro) inhibitor medicament.

Further, the coronavirus 3C L hydrolase (Mpro) inhibitor medicament is suitable for human or animal use.

Further, the animals include but are not limited to pets such as cats, dogs, parrots, fish or octopus.

The invention also protects the application of candesartan or pharmaceutically acceptable salts thereof in preparing a coronavirus 3C L hydrolase (Mpro) inhibitor medicament.

Further, the coronavirus 3C L hydrolase (Mpro) inhibitor medicament is suitable for human or animal use.

Further, the animals include but are not limited to pets such as cats, dogs, parrots, fish or octopus.

The invention also protects a novel medicament for preventing and/or treating coronavirus inflammation, which comprises one or more of candesartan cilexetil, pharmaceutically acceptable salt of candesartan cilexetil, candesartan or pharmaceutically acceptable salt of candesartan.

The invention also protects a coronavirus 3C L hydrolase (Mpro) inhibitor drug which comprises one or more of candesartan cilexetil, a pharmaceutically acceptable salt of candesartan cilexetil, candesartan or a pharmaceutically acceptable salt of candesartan.

Further, the coronavirus is a novel coronavirus (SARS-CoV-2).

Further, the medicine for preventing and/or treating the novel coronavirus inflammation and the coronavirus 3C L hydrolase (Mpro) inhibitor medicine are capsules, tablets, pills, granules, injections or sprays.

Further, the preventive and/or therapeutic agent for novel coronavirus inflammation, coronavirus 3C L hydrolase (Mpro) inhibitor agent is suitably used for human or animals.

Further, the animals include but are not limited to pets such as cats, dogs, parrots, fish or octopus.

Further, the medicine can also comprise a pharmaceutically acceptable carrier or auxiliary material.

Furthermore, the medicine for preventing and/or treating the novel coronavirus inflammation and the coronavirus 3C L hydrolase (Mpro) inhibitor medicine can be matched with other medicines for preventing and treating the novel coronavirus inflammation for use.

Compared with the prior art, the invention has the following beneficial effects:

the candesartan cilexetil and the hydrolysis product candesartan cilexetil of the invention have stronger bonding strength with a novel coronavirus target 3C L hydrolase (Mpro) which causes lung inflammation and the like, and can obviously inhibit the activity of 3C L hydrolase, wherein the candesartan cilexetil and the hydrolysis product candesartan cilexetil thereof have IC (integrated Circuit) of the 3C L hydrolase (Mpro)₅₀Respectively 2.78 +/-0.31 mu M and 9.45 +/-0.73 mu M, which shows that the candesartan cilexetil and the hydrolysis product of the candesartan cilexetil have the effect of preventing and treating pneumonia caused by novel coronavirus, and can be prepared into an anti-pneumonia medicament for application.

Drawings

Fig. 1 is a binding pattern of candesartan cilexetil with a novel coronavirus pneumonia target 3C L hydrolase (Mpro).

Figure 2 is a binding pattern of candesartan with a novel coronavirus pneumonia target 3C L hydrolase (Mpro).

Fig. 3 shows the results of inhibition of the novel coronavirus pneumonia target 3C L hydrolase (Mpro) by candesartan cilexetil and candesartan.

Detailed Description

The present invention will be explained in further detail below with reference to specific embodiments and the accompanying drawings. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as other examples would occur to those of skill in the art without the exercise of inventive faculty, and without the exercise of inventive faculty. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, reagents and materials which are commercially available.