CN113855670A

CN113855670A - Application of A205804 in preparation of medicine for treating sepsis

Info

Publication number: CN113855670A
Application number: CN202111296480.7A
Authority: CN
Inventors: 刘海鹏; 曹亚娟; 郑梦歌
Original assignee: Shanghai Pulmonary Hospital
Current assignee: Shanghai Pulmonary Hospital
Priority date: 2021-11-03
Filing date: 2021-11-03
Publication date: 2021-12-31
Anticipated expiration: 2041-11-03
Also published as: CN113855670B

Abstract

The invention provides application of A205804 in preparation of a medicament for treating sepsis, wherein the main active ingredient of the medicament is A205804 or pharmaceutically acceptable salt thereof. The invention verifies that the micromolecular drug A205804 can obviously prolong the survival period of a sepsis mouse and inhibit the release of sepsis inflammatory factors IL-6, IL-1 beta, TNF alpha, IFN beta and CXCL-10. Therefore, the A205804 has potential sepsis prevention and treatment values, and can be used for improving the cure rate of sepsis, improving the prognosis of patients and reducing medical resource consumption.

Description

Application of A205804 in preparation of medicine for treating sepsis

Technical Field

The invention relates to the field of biological medicines, and in particular relates to application of A205804 in preparation of a medicine for treating sepsis.

Background

Sepsis (sepsis) is a systemic inflammatory response syndrome caused by invasion of pathogenic microorganisms such as bacteria into the body, and has the characteristics of high morbidity, high fatality rate and high medical cost. According to epidemiological survey data, over 1900 ten thousand severe sepsis cases worldwide are shown each year, and the rate of onset is rising at 1.5% to 8.0% per year. Meanwhile, about 14,000 people die of sepsis and its complications every day worldwide, and become a leading cause of death of non-cardiac patients in intensive care units, and the surviving patients may have serious sequelae such as cognitive dysfunction. The sepsis treatment cost is high, the medical resource consumption is large, and great threat is caused to the human health.

The most effective approaches to sepsis are active systemic anti-inflammatory therapy, immunomodulatory therapy, and supportive therapy to ameliorate organ damage. In recent years, despite significant advances in anti-infective therapy and organ function support technologies, sepsis has still suffered from a mortality rate as high as 30% to 70%. Therefore, the treatment and prevention based on the pathogenesis of sepsis become the focus and hot spot of modern medical attention, however, the pathogenesis of sepsis is not completely elucidated at present, and the treatment and prevention relate to multiple aspects such as complex systemic inflammatory network effect, imbalance of immune function regulation, tissue damage, abnormal reaction of hosts to different infectious pathogenic microorganisms and toxins thereof, and the like. After the body is infected with pathogenic bacteria, local or systemic inflammatory reaction of a host is activated, a large amount of inflammatory mediators such as IL-6, IL-1 beta, TNF alpha, IFN beta, CXCL-10 and the like are generated and released, so that the immune function is unbalanced, and under the sepsis state, immunosuppression can further aggravate the systemic inflammatory reaction, so that the body can be subjected to multiple organ failure until death which cannot be reversed is realized.

Therefore, aiming at the pathogenesis of sepsis, the key problem to be solved urgently is to search for effective sepsis treatment and prevention medicines with clinical transformation value.

Each small molecule drug has a mechanism for its action, is suitable for different groups, and cannot cover all patients with sepsis. Therefore, there is a need to further search for the mechanism of action of small molecule drugs, as well as more effective sepsis therapeutic drugs.

A205804 is a small molecule compound, the molecular structure of which is shown in figure 1, and the existing research shows that the A205804 is used for the research of chronic inflammatory diseases, can obviously reduce the number of mouse peripheral blood leukocytes under inflammatory conditions, and the adhesion molecules mediate the rolling adhesion of the leukocytes on endothelial cells, and the A205804 can obviously reduce the rolling adhesion of human promyelocytic leukemia cells (HL-60) on Human Umbilical Vein Endothelial Cells (HUVECs) activated by TNF alpha, and inhibit the expression of adhesion molecule family members, namely integrin E-selectin and intercellular adhesion molecule ICAM-1. However, no relevant study for the treatment of sepsis is available with a 205804.

Disclosure of Invention

In order to overcome the defects in the prior art, the invention provides application of A205804 in preparing a medicament for treating sepsis.

In order to achieve the purpose, the invention adopts the following technical scheme:

the first aspect of the invention provides a small molecule compound for treating sepsis, wherein the small molecule compound is A205804 shown in a structural formula I or a pharmaceutically acceptable salt thereof:

the second aspect of the invention provides a medicament for inhibiting sepsis inflammatory response, which mainly comprises the active ingredients of A205804 shown in the structural formula I or pharmaceutically acceptable salts thereof:

further, the medicine also comprises a pharmaceutically acceptable carrier or excipient.

The third aspect of the invention provides an application of A205804 in preparing a medicament for treating sepsis, wherein the main active ingredient of the medicament is A205804 shown in a structural formula I or a pharmaceutically acceptable salt thereof:

Further, the above drugs, after administration, can exert the following effects:

(a) remarkably inhibiting the expression of inflammatory factors IL-6, CXCL-10 and IFN-beta; and

(b) prolonging the life span.

Further, the administration route of the above drugs is oral, transdermal, intramuscular, subcutaneous or intravenous injection.

Furthermore, the dosage form of the medicine can be tablets, capsules, oral liquid, buccal agents, granules, medicinal granules, pills, powder, paste, pellets, suspensions, powder, solutions, injections, creams, sprays, drops or patches.

The fourth aspect of the invention provides an application of A205804 in preparation of a medicament for inhibiting sepsis inflammatory reaction, wherein the main active ingredient of the medicament is A205804 shown in a structural formula I or a pharmaceutically acceptable salt thereof:

(b) prolonging the life span.

By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:

the invention verifies that the micromolecular drug A205804 can obviously prolong the survival period of a sepsis mouse and inhibit the release of sepsis inflammatory factors IL-6, IL-1 beta, TNF alpha, IFN beta and CXCL-10. Therefore, the A205804 has potential sepsis prevention and treatment values, and can be used for improving the cure rate of sepsis, improving the prognosis of patients and reducing medical resource consumption.

Drawings

FIG. 1 is a schematic representation of the 2D (Panel A) and 3D (Panel B) molecular structures of small molecule Compound A205804;

FIG. 2 shows that A205804 inhibits the sepsis inflammatory response of macrophages (MPMs) in the abdominal cavity of mice in one embodiment of the present invention; wherein, the graph A shows that A205804 remarkably inhibits the expression of inflammatory factors IL-6, CXCL-10 and IFN-beta induced by LPS, and is dose-dependent; panel B shows that a205804 significantly inhibited ISD-induced expression of the inflammatory factors CXCL-10 and IFN- β, and was dose-dependent; panel C shows that a205804 significantly inhibited cgamp-induced expression of the inflammatory factors CXCL-10 and IFN- β, and was dose-dependent; panel D shows that A205804 significantly inhibited PolyI C-induced expression of inflammatory factors IL-6, CXCL-10 and IFN- β, and was dose dependent;

FIG. 3 shows the survival observations of A205804 intervened in sepsis mice in one embodiment of the invention; wherein, the graph A is a sepsis mouse model experiment flow, the graph B shows the survival period observation result of the sepsis mouse induced by the intervention of A205804 on LPS, and the graph C shows the survival period observation result of the sepsis mouse induced by the intervention of A205804 on PolyI and C;

FIG. 4 shows the results of RT-PCR assay of the expression of inflammatory cytokines IL-6, CXCL-10, IFN-. beta.and TNF. alpha in mouse liver (panel A), lung (panel B), spleen (panel C) tissues in one embodiment of the present invention.

Detailed Description

The invention provides application of A205804 in preparation of a medicament for treating sepsis, wherein the main active ingredient of the medicament is A205804 shown in a structural formula I or pharmaceutically acceptable salt thereof:

in a preferred embodiment of the present invention, the above-mentioned medicament further comprises a pharmaceutically acceptable carrier or excipient.

The term "pharmaceutically acceptable salt" refers to salts of the compounds with pharmaceutically acceptable inorganic or organic acids, including but not limited to: hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid; such organic acids include, but are not limited to: formic acid, acetic acid, propionic acid, succinic acid, 1, 5-naphthalenedisulfonic acid, sulfinic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethylacetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, adipic acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, and amino acids; by "pharmaceutically acceptable" is meant a material that is suitable for use in humans without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.

The term "carrier or excipient" includes one or more of binders, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavouring agents, wetting agents and the like.

The present invention will be described in detail and specifically with reference to the following examples and drawings so as to provide a better understanding of the invention, but the following examples do not limit the scope of the invention.

In the examples, the conventional methods were used unless otherwise specified, and reagents used were those conventionally commercially available or formulated according to the conventional methods without specifically specified.

Example 1

This example demonstrates the inhibition of sepsis inflammatory response by A-205804 at the in vitro cytological level, and the specific procedures and results are as follows:

1.LPS (100ng/ml) is adopted to stimulate macrophages in abdominal cavity of the mouse for 2 hours, inflammatory response is induced, and small molecule medicine A205804 with different concentrations (0, 0.01, 0.1, 1 and 10 mu M) is given for treatment.

As can be seen from FIG. 2A, A205804 can significantly inhibit LPS-induced expression of inflammatory factors IL-6, CXCL-10 and IFNB, and the inhibition effect represents drug dose dependence.

2. Innate immunity is the first line of defense of the body against infection by foreign pathogens, and excessive activation leads to sepsis, autoimmune diseases, and the like, and mainly comprises a Toll-like receptor for recognizing pathogenic RNA and a cGAS-STING signaling pathway for recognizing DNA. Therefore, in addition to the initiation of inflammatory response by inducing TLR4 with LPS, we also used different signal pathway stimulators including ISD (cGAS agonist, FIG. 2B), cgamp (STING agonist, FIG. 2C), PolyI: C (Toll-like receptor TLR3 agonist, FIG. 2D) to activate innate immune target genes to initiate downstream inflammatory response, and similarly treated with different concentrations (0, 0.01, 0.1, 1, 10. mu.M) of small molecule drug A205804.

As can be seen from FIGS. 2B-D, the results are consistent with the inflammatory response induced by LPS, suggesting that A205804 can significantly inhibit the expression of inflammatory factors IL-6, CXCL-10 and IFN- β, and is dose-dependent.

In conclusion, in cytology level, A205804 is a small molecule drug which is effective in inhibiting sepsis inflammatory response.

Example 2

This example demonstrates inhibition of sepsis inflammatory response by a205804 at the in vivo animal level, with the following specific procedures and results:

LPS induces an acute systemic inflammatory response, and D-galactosamine (D-gal) is often used in combination with LPS to rapidly amplify the LPS effect, exacerbating sepsis development. The mouse sepsis model is induced by large dose, combined use and single intraperitoneal injection of LPS and D-gal with lethal dose, the method is highly controllable and has good repeatability, and the systemic acute inflammatory response of a host to sepsis can be observed. Based on the weight conversion, 1ng of LPS and 7.5mg of D-gal are given to the mice to induce sepsis in an intraperitoneal injection mode, an A20580410 mg/kg dose is given to the mice to perform intraperitoneal injection intervention at the same time, the time is 8 hours, and an experimental flow chart is shown in a figure 3A. First we observed the survival of mice and studies showed that a205804 significantly extended the survival of LPS-induced sepsis mice (fig. 3B). In addition, 40 mug of PolyI and 7.5mg of combined D-gal are injected intraperitoneally to induce the sepsis of the mice, and the A205804 is injected intraperitoneally at the same time, the experimental flow chart is shown in figure 3A, and the research also shows that the A205804 can remarkably prolong the survival period of the sepsis mice induced by the PolyI and C (figure 3C).

2. In order to further observe the effect of A205804 on systemic inflammatory response of a sepsis mouse, 6 hours after the mice are induced with sepsis by interfering LPS and D-gal through A205804, respectively taking liver, lung and spleen tissues of the mice, performing an RT-PCR experiment, and detecting the expression of inflammatory cytokines IL-6, CXCL-10, IFN-beta and TNF alpha. The results show that A205804 can inhibit the expression of inflammatory cytokines IL-6, CXCL-10, IFN-beta and TNF alpha in mouse liver (FIG. 4A), lung (FIG. 4B) and spleen (4C) tissues to different degrees.

In conclusion, at the animal level in vivo, a205804 is also a small molecule drug effective in inhibiting sepsis inflammatory responses.

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. It will be appreciated by those skilled in the art that any equivalent modifications and substitutions are 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.

Claims

1. A small molecule compound for treating sepsis, wherein the small molecule compound is A205804 represented by the structural formula I:

2. a medicament for inhibiting sepsis inflammatory reaction is characterized in that the main active ingredient of the medicament is A205804 shown in a structural formula I or pharmaceutically acceptable salt thereof:

3. the medicament of claim 2, further comprising a pharmaceutically acceptable carrier or excipient.

The application of A205804 in preparing the medicine for treating sepsis is characterized in that the main active ingredient of the medicine is A205804 shown in a structural formula I or a pharmaceutically acceptable salt thereof:

the application of A205804 in preparing the medicament for inhibiting sepsis inflammatory reaction is characterized in that the main active ingredient of the medicament is A205804 shown in a structural formula I or pharmaceutically acceptable salt thereof:

6. the use according to claim 4 or 5, wherein the medicament further comprises a pharmaceutically acceptable carrier or excipient.

7. The use according to claim 4 or 5, wherein the medicament, after administration, exerts the following effects:

(b) prolonging the life span.

8. Use according to claim 4 or 5, wherein the route of administration of the medicament is oral, transdermal, intramuscular, subcutaneous or intravenous injection.

9. The use according to claim 4 or 5, wherein the medicament is in the form of tablets, capsules, oral liquids, buccal agents, granules, pills, powders, ointments, pellets, suspensions, powders, solutions, injections, creams, sprays, drops or patches.