Use of a compound targeting the inhibition of PDE4B for the preparation of a medicament for the prevention and / or treatment of sepsis

Abstract

The application discloses application of a compound for targeting and inhibiting PDE4B in preparation of a medicine for preventing and / or treating sepsis. The PDE4B selective inhibitor, especially the BR compound, has remarkable curative effect on improving survival rate of sepsis and protecting multiple organ functions, has no obvious side effect, is safer than a non-selective PDE4 inhibitor, provides a clear direction for development of a medicine for treating sepsis, and has a wide clinical application prospect.

Description

Technical Field

[0001] This application relates to the field of biomedical technology, and in particular to the use of a compound that targets and inhibits PDE4B in the preparation of a medicament for the prevention and / or treatment of sepsis. Background Technology

[0002] Sepsis is a disease caused by infection that triggers an dysregulation of the host's immune response, leading to life-threatening organ dysfunction. Its pathological process is centered on uncontrolled systemic inflammatory response, abnormal cell function, and tissue damage, eventually progressing to multiple organ failure.

[0003] Current treatment options for sepsis still have significant limitations, mainly focusing on supportive care, lacking effective specific drugs, and suffering from problems such as poor targeting and significant side effects. Summary of the Invention

[0004] This application provides the use of a compound that targets and inhibits PDE4B in the preparation of drugs for the prevention and / or treatment of sepsis, which can solve the problems of poor targeting and obvious side effects of existing sepsis treatment drugs.

[0005] In one aspect, this application provides the use of a compound that targets and inhibits PDE4B in the preparation of a medicament for the prevention and / or treatment of sepsis.

[0006] In any embodiment of this application, the compound that targets and inhibits PDE4B includes a selective PDE4B inhibitor.

[0007] In any embodiment of this application, the selective PDE4B inhibitor includes at least one of namisitol, BR class compounds, compound I, compound II, compound A2-A4, and compound B2-B4; Among them, the chemical structure of BR-type compounds is as follows: , L is selected from a single bond or optionally from a C1-C3 alkylene group substituted with one or more substituents selected from -D, halogen, C1-C3 alkyl, or C1-C3 alkoxy; R1 is selected from -D, -H, halogen, -OH, -CN, -CHO, -OR5, -OC(O)R5, -COOR5, -NR6R7, -CONR6R7, -SR5, -SOR5, -SO2NR6R7, -CH=NOR8, or R5 is independently selected from -D, -H, C1-C 15 Alkyl or benzo[a]heterocyclic group, C1-C 15 Alkyl or benzo[a]heterocyclic group may be optionally surrounded by one or more groups selected from -D, halogen, -OH, -NH2, C1-C5 alkyl, , The substituents of R6 and R7 are each independently selected from -D, -H, -OH, -CN, C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5 alkyl, the C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5 alkyl optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5 alkoxy, or R6 and R7 are connected together with the N atom to which they are attached to form a 3-10 membered heterocyclic alkyl, and the 3-10 membered heterocyclic alkyl is optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy or hydroxyl-substituted C1-C6 alkyl, and R8 is selected from -D, -H or -COR5; R2 is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10-membered heteroaryl, wherein the 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, C6-C 10 The aryl group, or 5-10 heteroaryl group, is optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, hydroxy-substituted C1-C5 alkyl, C1-C3 alkyl-O-C1-C3 alkyl, -CO-C1-C5 alkyl, -CONR6R7, C1-C5 haloalkyl, C2-C5 haloalkenyl, C1-C5 haloalkoxy, hydroxy-substituted C1-C5 haloalkyl, C1-C3 haloalkyl-O-C1-C3 haloalkyl or -CO-C1-C5 haloalkyl; R3 and R4 are independently selected from -D, -H, halogen, -OH or C1-C6 alkyl, X is selected from -O-, -S-, -SO-, -SO2- or -CO-, Y is selected from -CH2- or -NR6-, and n is 0 or 1; The chemical structure of compound I is X is selected from O, S and NR. 7 ;R 1 R 2 R 4 R 5 R 7 R 9 and R 10 Independently selected from hydrogen, acyl, optionally substituted low-carbon alkyl, optionally substituted low-carbon alkenyl, optionally substituted low-carbon ynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaryl. However, the condition is R1 and R 2 、or R 4 and R 5 、or R 9 and R 10 、or R 2 and R 3 They can combine to form optionally substituted heterocycles; R 3 Selected from cyano, nitro, -C(Z)R 8 S(O2)NR 9 R 10 -S(O2)R 11 and optionally substituted low-carbon alkyl groups; Y and Z are independently selected from O and S; R 6 and R 8 Selected from hydroxyl, alkoxy, thioalkoxy, optionally substituted amine, optionally substituted low carbon alkyl, optionally substituted low carbon alkenyl, optionally substituted low carbon alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl and optionally substituted heterocycle; and R 11 Independently selected from hydroxyl, alkoxy, thioalkoxy, optionally substituted low carbon alkyl, optionally substituted low carbon alkenyl, optionally substituted low carbon alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaryl; and their salts, prodrugs and isomers; The chemical structure of compound II is as follows: Ring A is a 5-10 membered aromatic ring or heteroaromatic ring; B is selected from 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, or 3-10 membered cycloalkyl; R a and R b Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 alkyl carbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3- to 10-membered heterocyclic alkyl; C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkynyl group, C1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 alkyl carbonyl, C 1-6 Alkoxy and C 1-6 The haloalkoxy group is optionally surrounded by one or more R c Replace; the R c Substituents selected from the following: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 alkyl carbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; when the substituent R c When there are multiple R, the R c Same or different; m and n are 0, 1, 2 or 3 respectively; Y is selected from NR 1 O, S or CHR 1 ; R 1 Selected from H, C 1-10 Alkyl, C 2-6 alkenyl, C 1-10 Alkyl, C 2-6 Alkenyl groups are optionally separated by one or more R groups d Replace; R d Substituents selected from the following: halogen, C 1-3 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -COO-C 1-6 Alkyl, -C(O)NR f R f 5-8 Yuanfanghuan, -het 1 Single or double ring-C 5-8 -cycloalkyl; wherein, the R f For hydrogen, C 1-6 Alkyl; het 1 This refers to a 5-8 member monocyclic or bicyclic, saturated or unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, S, and O. Compounds A2 to A4 include ; Compounds B2-B4 include .

[0008] In any embodiment of this application, the compound that targets and inhibits PDE4B includes at least one of siRNA, sgRNA, dsRNA, shRNA, miRNA, antisense nucleic acid, antibody, and enzyme that targets PDE4B.

[0009] In any embodiment of this application, the compound that targets and inhibits PDE4B satisfies at least one of the following conditions: (1) It can inhibit PDE4B enzyme activity; (2) It can reduce the content of PDE4B enzyme.

[0010] In any embodiment of this application, sepsis includes at least one of bacterial sepsis, fungal sepsis, and viral sepsis.

[0011] In any embodiment of this application, sepsis includes functional damage to an organ, which includes at least one of sepsis-induced lung injury, myocardial dysfunction, liver injury, kidney injury, and microcirculatory disturbance.

[0012] In any embodiment of this application, prevention and / or treatment of sepsis includes at least one of the following: reducing the wet-to-dry weight ratio of the lungs, improving vascular permeability, reducing alveolar septal thickness, reducing the infiltration area of ​​myeloid cells, restoring blood perfusion to the heart and hind limbs, improving cardiac systolic function, improving cardiac diastolic function, reducing the expression of liver and kidney function damage markers, and reducing the expression level of inflammatory factors.

[0013] In any embodiment of this application, the drug also includes a pharmaceutically acceptable carrier, excipient, or salt.

[0014] In any embodiment of this application, the drug contains 0.01%-99.5% by weight of the compound that targets and inhibits PDE4B.

[0015] In any embodiment of this application, the dosage form of the drug includes a gastrointestinal dosage form or a non-gastrointestinal dosage form.

[0016] In any embodiment of this application, the route of administration of the drug includes gastrointestinal administration or non-gastrointestinal administration.

[0017] The application of the compound that targets and inhibits PDE4B in the embodiments of this application in the preparation of drugs for the prevention and / or treatment of sepsis shows that the compound has stronger targeting, higher safety, no obvious toxic side effects, and can effectively treat sepsis. Attached Figure Description

[0018] To more clearly illustrate the technical solutions of the embodiments of this application, the accompanying drawings used in the embodiments of this application will be briefly introduced below. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 This is an image showing the expression characteristics of PDE4B in the lung tissue of septic mice in Example 1 of this application (where A is a heatmap of PDE family gene expression in the lung tissue of mice in the 12h and 24h groups after septic modeling (CLP) and the sham-operated group; B is the relative mRNA expression levels of PDE4A, PDE4B, PDE4C, and PDE4D in wild-type mice 12h and 24h after CLP in wild-type mice detected by RT-qPCR (n=6 / group); CD is the expression and quantification of PDE4B protein in wild-type mice 12h and 24h after CLP in wild-type mice detected by Western blot (n=6 / group); E is the immunofluorescence detection of mouse lung tissue samples, showing the expression of PDE4B (red) in vascular endothelial cells (CD31+, green) and myeloid cells (MPO+, cyan) (blue: DAPI, n=3 / group)).

[0020] Figure 2 This is a schematic diagram illustrating the effect of PDE4B gene deletion on the survival and organ function of septic mice in Example 2 of this application (wherein, Figure A shows the survival curves of wild-type mice (PDE4B+ / +) and PDE4B KO mice (PDE4B- / -) 7 days after CLP surgery (n=19 / WT, n=20 / KO); Figure B shows the wet-to-dry weight ratio of the lungs (n=6 / group); Figure C shows the quantitative Evans blue content in lung tissue (n=6 / group); Figure D shows a representative image of HE staining in lung tissue (Bar=50μm); Figure E shows the quantitative alveolar septum thickness (n=6 / group); Figures G and F show representative images of MPO immunofluorescence staining in lung tissue and the quantitative positive area (n=6 / group, Bar=50μm); Figure HJ shows the laser Doppler detection and quantitative analysis of blood perfusion in the heart and hind limb skin (n=6 / sham-operated group, n=8 / CLP). (n=6 / group); KL plot shows the left ventricular ejection fraction and cardiac output of mice as detected by echocardiography (n=6 / group); MP plot shows the plasma urea nitrogen, creatinine, alanine aminotransferase and aspartate aminotransferase levels of mice (n=6-7 / group); QR plot shows the plasma tumor necrosis factor-α and interleukin-1-β levels (n=8-10 / group).

[0021] Figure 3This is a schematic diagram illustrating the therapeutic effects of PDE4B inhibitors on septic mice (Figure A shows the 7-day survival curves after CLP in the solvent group, roflumilast group, and BR29175 group (n=19 / solvent group, roflumilast group, n=18 / BR29175 group, n=8 / sham-operated group); Figure B shows the clinical symptom scores of sepsis in mice after CLP in each group (AUC=0 in the Sham group; AUC=43.82 in the solvent group); AUC=22.80 in the roflumilast group; AUC=21.77 in the BR29175 group; Figure C shows the wet-to-dry weight ratio of the lungs (n=13 / solvent group, roflumilast group, BR29175 group, n=8 / sham-operated group); Figure D shows the quantitative analysis of Evans blue dye content in lung tissue (n=6 / Figure 1 shows the lung tissue hematoxylin / eosin staining and MPO immunofluorescence staining (Bar=50μm); Figure 2 shows the alveolar septum thickness quantification (n=6 / group); Figure 3 shows the lung tissue MPO immunofluorescence staining and positive area quantification (n=6 / group); Figure 4 shows the laser Doppler detection and quantification of blood perfusion in the mouse heart and hind limb skin (n=8 / sham-operated group, n=8 / solvent group, n=9 / roflumilast group, BR29175 group); Figure 5 shows the echocardiographic detection of left ventricular ejection fraction and cardiac output in mice (n=6 / sham-operated group, solvent group, n=8 / roflumilast group, BR29175 group); Figure 6 shows the plasma urea nitrogen, creatinine, alanine aminotransferase, and aspartate aminotransferase levels in mice (n=6 / group); Figure 7 shows the plasma tumor necrosis factor-α and interleukin-1-β levels (n=6 / sham-operated group, n=8 / group). / Solvent group, Roflumilast group, BR29175 group).

[0022] Figure 4 This is a schematic diagram of the effect of drug injection on the activity level of mice (where AD graphs represent images collected sequentially at 30-second intervals from the starting point of the video recording). Detailed Implementation

[0023] To make the purpose, technical solution, and beneficial technical effects of this application clearer, the following detailed description is provided in conjunction with embodiments. It should be understood that the implementation details described in this specification are merely for illustrative purposes and are not intended to limit the scope of this application.

[0024] For simplicity, this application only explicitly discloses some numerical ranges. However, any lower limit can be combined with any upper limit to form a range not explicitly stated; and any lower limit can be combined with other lower limits to form a range not explicitly stated, just as any upper limit can be combined with any other upper limit to form a range not explicitly stated. Furthermore, although not explicitly stated, every point or individual value between the endpoints of the range is included within that range. Therefore, each point or individual value can be used as its own lower or upper limit and combined with any other point or individual value or with other lower or upper limits to form a range not explicitly stated.

[0025] It should be noted that the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitations, an element defined by the phrase "comprising..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0026] Unless otherwise stated, the values ​​of the parameters mentioned in this application can be measured using various measurement methods commonly used in the art (e.g., they can be tested according to the methods given in the embodiments of this application). Unless otherwise stated, the test temperature for all parameters mentioned in this application is 25°C and the test pressure is standard atmospheric pressure.

[0027] The foregoing description of this application is not intended to describe every disclosed implementation or method. Instead, the following description provides more specific examples of exemplary embodiments. Throughout the application, guidance is provided through a series of embodiments, which can be used in various combinations. The examples listed are representative only and should not be construed as exhaustive.

[0028] In view of the aforementioned problems in the prior art, this application provides the use of a compound that targets and inhibits PDE4B in the preparation of a drug for the prevention and / or treatment of sepsis, which can solve the problems of poor targeting and obvious side effects of existing sepsis treatment drugs.

[0029] The first aspect of this application provides the use of a compound that targets and inhibits PDE4B in the preparation of a medicament for the prevention and / or treatment of sepsis.

[0030] Compounds that target and inhibit PDE4B can be prepared as the sole active ingredient in drugs for the treatment of sepsis.

[0031] Compounds that target and inhibit PDE4B can also be combined with other components as active ingredients to prepare drugs for sepsis.

[0032] In some implementations, compounds that target and inhibit PDE4B include selective PDE4B inhibitors.

[0033] In some embodiments, the selective PDE4B inhibitor includes at least one of namisitol, BR compounds, compounds of formula I, compounds of formula II, compounds A2-A4, and compounds B2-B4; Among them, the chemical structure of BR-type compounds is as follows: , L is selected from a single bond or optionally from a C1-C3 alkylene group substituted with one or more substituents selected from -D, halogen, C1-C3 alkyl, or C1-C3 alkoxy; R1 is selected from -D, -H, halogen, -OH, -CN, -CHO, -OR5, -OC(O)R5, -COOR5, -NR6R7, -CONR6R7, -SR5, -SOR5, -SO2NR6R7, -CH=NOR8, or R5 is independently selected from -D, -H, C1-C 15 Alkyl or benzo[a]heterocyclic group, C1-C 15 Alkyl or benzo[a]heterocyclic group may be optionally surrounded by one or more groups selected from -D, halogen, -OH, -NH2, C1-C5 alkyl, , The substituents of R6 and R7 are each independently selected from -D, -H, -OH, -CN, C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5 alkyl, the C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5 alkyl optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5 alkoxy, or R6 and R7 are connected together with the N atom to which they are attached to form a 3-10 membered heterocyclic alkyl, and the 3-10 membered heterocyclic alkyl is optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy or hydroxyl-substituted C1-C6 alkyl, and R8 is selected from -D, -H or -COR5; R2 is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10-membered heteroaryl, wherein the 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, C6-C 10The aryl group, or 5-10 heteroaryl group, is optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, hydroxy-substituted C1-C5 alkyl, C1-C3 alkyl-O-C1-C3 alkyl, -CO-C1-C5 alkyl, -CONR6R7, C1-C5 haloalkyl, C2-C5 haloalkenyl, C1-C5 haloalkoxy, hydroxy-substituted C1-C5 haloalkyl, C1-C3 haloalkyl-O-C1-C3 haloalkyl or -CO-C1-C5 haloalkyl; R3 and R4 are independently selected from -D, -H, halogen, -OH or C1-C6 alkyl, X is selected from -O-, -S-, -SO-, -SO2- or -CO-, Y is selected from -CH2- or -NR6-, and n is 0 or 1; The chemical structure of compound I is X is selected from O, S and NR. 7 ;R 1 R 2 R 4 R 5 R 7 R 9 and R 10 Independently selected from hydrogen, acyl, optionally substituted low-carbon alkyl, optionally substituted low-carbon alkenyl, optionally substituted low-carbon ynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaryl. However, the condition is R 1 and R 2 、or R 4 and R 5 、or R 9 and R 10 、or R 2 and R 3 They can combine to form optionally substituted heterocycles; R 3 Selected from cyano, nitro, -C(Z)R 8 S(O2)NR 9 R 10 -S(O2)R 11 and optionally substituted low-carbon alkyl groups; Y and Z are independently selected from O and S; R 6 and R 8Selected from hydroxyl, alkoxy, thioalkoxy, optionally substituted amine, optionally substituted low carbon alkyl, optionally substituted low carbon alkenyl, optionally substituted low carbon alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl and optionally substituted heterocycle; and R 11 Independently selected from hydroxyl, alkoxy, thioalkoxy, optionally substituted low carbon alkyl, optionally substituted low carbon alkenyl, optionally substituted low carbon alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaryl; and their salts, prodrugs and isomers; The chemical structure of compound II is as follows: Ring A is a 5-10 membered aromatic ring or heteroaromatic ring; B is selected from 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, or 3-10 membered cycloalkyl; R a and R b Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 alkyl carbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3- to 10-membered heterocyclic alkyl; C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 alkyl carbonyl, C 1-6 Alkoxy and C 1-6 The haloalkoxy group is optionally surrounded by one or more R c Replace; the R c Substituents selected from the following: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 alkyl carbonyl, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups; when the substituent R c When there are multiple R, the R c Same or different; m and n are 0, 1, 2 or 3 respectively; Y is selected from NR 1 O, S or CHR 1 ; R 1 Selected from H, C 1-10 Alkyl, C 2-6 alkenyl, C 1-10 Alkyl, C 2-6 Alkenyl groups are optionally separated by one or more R groups d Replace; R d Substituents selected from the following: halogen, C 1-3 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -COO-C 1-6 Alkyl, -C(O)NR f R f 5-8 Yuanfanghuan, -het 1 Single or double ring-C 5-8 -cycloalkyl; wherein, the R f For hydrogen, C 1-6 Alkyl; het 1 This refers to a 5-8 member monocyclic or bicyclic, saturated or unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, S, and O. Compounds A2 to A4 include ; Compounds B2-B4 include .

[0034] It should be noted that the chemical structure of the BR-type compounds in this application has the structure of the compound of Formula I as described in patent application number CN202411173731.6. As an example, the chemical structure of the BR-type compounds in this application can be... or Preferred .

[0035] It should be noted that the chemical structure of the compound of formula I in this application has the structure of the compound of formula I as described in patent application number CN200580022054.7. As an example, the chemical structure of the compound of formula I in this application includes at least one of compounds 1-1 to 1-260 listed in Table 1A of patent application number CN200580022054.7.

[0036] It should be noted that the chemical structure of the compound of formula II in this application has the structure of the compound of formula II as described in patent application number CN202310724689.1. As an example, the chemical structure of the compound of formula II in this application includes at least one of the compounds listed in claims 25 to 27 of patent application number CN202310724689.1.

[0037] In some embodiments, compounds that target and inhibit PDE4B include at least one of siRNA, sgRNA, dsRNA, shRNA, miRNA, antisense nucleic acid, antibody, and enzyme that target PDE4B.

[0038] Preferably, the compound that targets and inhibits PDE4B includes siRNA that targets PDE4B.

[0039] In some embodiments, the compound that targets and inhibits PDE4B satisfies at least one of the following conditions: (1) It can inhibit PDE4B enzyme activity; (2) It can reduce the content of PDE4B enzyme.

[0040] PDE4B is a hydrolase belonging to the phosphodiesterase (PDE) superfamily. PDE4B specifically hydrolyzes the intracellular second messenger cyclic adenosine monophosphate (cAMP), degrading it to 5'-AMP, thereby terminating downstream cAMP signaling (such as the PKA pathway). The PDE4 family consists of cAMP-specific hydrolases, including four subtypes: PDE4A, PDE4B, PDE4C, and PDE4D. PDE4B enhances cAMP hydrolysis, exacerbating neutrophil activation, microvascular dysfunction, and myocardial ischemia-reperfusion injury. However, the role and mechanism of PDE4B in sepsis remain unclear. Existing sepsis treatments have significant limitations. For example, the non-selective PDE4 inhibitor roflumilast inhibits all PDE4 subtypes, easily causing side effects such as diarrhea, nausea, and weight loss, limiting its application in sepsis. Therefore, developing more targeted and safer sepsis treatments has become an urgent clinical need.

[0041] In some embodiments, sepsis includes at least one of bacterial sepsis, fungal sepsis, and viral sepsis.

[0042] In some embodiments, sepsis includes functional damage to organs, including at least one of sepsis-induced lung injury, myocardial dysfunction, liver injury, kidney injury, and microcirculatory disturbance.

[0043] In some implementations, prevention and / or treatment of sepsis includes at least one of the following: reducing the wet-to-dry weight ratio of the lungs, improving vascular permeability, reducing alveolar septal thickness, reducing the infiltration area of ​​myeloid cells, restoring blood perfusion to the heart and hind limbs, improving cardiac systolic function, improving cardiac diastolic function, reducing the expression of liver and kidney function damage markers, and reducing the expression levels of inflammatory factors.

[0044] In some embodiments, the drug also includes a pharmaceutically acceptable carrier, excipient, or salt.

[0045] In some embodiments, the drug may contain 0.01%-99.5% by weight (specifically, 0.01%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%) of the compound that targets and inhibits PDE4B.

[0046] In some embodiments, the dosage form of the drug includes a gastrointestinal dosage form or a non-gastrointestinal dosage form.

[0047] In some implementations, the route of administration of the drug includes gastrointestinal administration or non-gastrointestinal administration.

[0048] The dosage of the drug is 1 mg / kg to 100 mg / kg (e.g., 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg), and may be adjusted according to clinical observation results.

[0049] The drug administration cycle is 1 to 10 weeks (e.g., 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks), and may be adjusted according to clinical observation results.

[0050] The "medicine" described in this application can be used to treat humans or non-human animals, such as non-human mammals. The medicine may contain pharmaceutically acceptable carriers, excipients, or salts commonly found in the art.

[0051] As an example, the excipients are selected from at least one of diluents, adhesives, lubricants, and wetting agents.

[0052] Optionally, the drug can be in any suitable dosage form, such as a gastrointestinal or non-gastrointestinal dosage form, preferably including but not limited to tablets, pills, powders, granules, capsules, lozenges, syrups, liquids, emulsions, microemulsions, suspensions, injections, sprays, aerosols, powder inhalers, lotions, ointments, plasters, pastes, patches, eye drops, nasal drops, sublingual tablets, suppositories, aerosols, effervescent tablets, pellets, gels, etc. Various dosage forms of the drug can be prepared according to conventional pharmaceutical manufacturing methods.

[0053] As an example, the dosage form of a drug includes at least one of tablets, capsules, granules, suspensions, pellets, injections, and aerosols.

[0054] The drug can be administered via any suitable route of administration, such as gastrointestinal (e.g., oral) or non-gastrointestinal (e.g., intravenous, intramuscular, subcutaneous, intradermal, intra-organ, intranasal, intraocular, intravenous, intracerebral, intrathecal, transdermal, rectal, etc.).

[0055] In addition to using the aforementioned compounds that target and inhibit PDE4B (existing or under development, as well as commercially available PDE4B inhibitors) to prevent and / or treat sepsis, this application also proposes using gene editing technologies (such as CRISPR-Cas9, TALENs, ZFNs, single-base editing systems, etc.) to directly knock out or mutate the target gene to inactivate the target and thus prevent and / or treat sepsis. The aforementioned target gene can be understood as the PDE4B gene.

[0056] It should be noted that inhibitors, blocking agents, inactivating agents, mutagenizers, and interferon developed based on biological methods (including gene introduction, gene editing, etc.) can also be used to prevent and / or treat the aforementioned sepsis.

[0057] The selective PDE4B inhibitors of this invention, especially BR compounds, have significant efficacy in improving sepsis survival and protecting multiple organ functions, with no obvious side effects. Compared with non-selective PDE4 inhibitors (such as roflumilast), they are safer, providing a clear direction for the development of sepsis treatment drugs and have broad clinical application prospects.

[0058] This invention demonstrates, through the construction of a mouse sepsis-related model, that compounds targeting and inhibiting PDE4B are highly effective in treating sepsis. Specifically, selective PDE4B inhibitors significantly reduce the wet-to-dry weight ratio of the lungs, improve vascular permeability, reduce alveolar septal thickness and myeloperoxidase (MPO) infiltration, restore cardiac and hindlimb blood perfusion, improve cardiac systolic and diastolic function, and reduce the expression levels of liver and kidney function damage markers (such as aspartate aminotransferase, alanine aminotransferase, creatinine, and blood urea nitrogen) and inflammatory factors (such as tumor necrosis factor-α and interleukin-1-β). Compared with existing non-selective PDE4 inhibitors, the PDE4B-targeting inhibitors of this invention exhibit superior therapeutic effects at the same dose, specifically with better safety and fewer side effects (such as transient drowsiness and decreased activity).

[0059] The term "pharmaceutically acceptable" as used in this application refers to the biological activity and characteristics of the active substance in the applied product that neither significantly stimulates the organism nor inhibits it.

[0060] The term "treatment" as used in this application means slowing, interrupting, preventing, controlling, stopping, reducing, or reversing a sign, symptom, disorder, condition, or progression or severity of a disease after it has begun to develop, but does not necessarily involve the complete elimination of all disease-related signs, symptoms, conditions, or disorders.

[0061] The term "prevention" as used in this application refers to a method implemented to prevent or delay the occurrence of a disease, condition, or symptom in the body.

[0062] Example The following embodiments describe the disclosure of this application in more detail. These embodiments are for illustrative purposes only, as various modifications and variations will be apparent to those skilled in the art within the scope of the disclosure of this application. Unless otherwise stated, all parts, percentages, and ratios reported in the following embodiments are based on mass, and all reagents used in the embodiments are commercially available or synthesized by conventional methods and can be used directly without further processing, and the instruments used in the embodiments are commercially available.

[0063] Example 1: Expression characteristics of PDE4B in sepsis I. Construction of a mouse sepsis model: A mouse model of multibacterial sepsis was established using the cecal ligation and puncture (CLP) method. Wild-type mice (C57BL / 6J) used in the experiment were purchased from Beijing Huafukang Biotechnology Co., Ltd. 1. Anesthesia: Mice were anesthetized by inhalation with 1.5-2.5% isoflurane (100% oxygen, 1L / min). The procedure was started after squeezing the mouse's toes to confirm that the mouse did not respond. 2. Surgical procedure: The mouse's abdomen was shaved and disinfected. The skin and peritoneum were incised along the midline (about 1 cm). The cecum was removed, and 75% of the cecum was ligated with 6-0 silk sutures (avoiding the ileocecal valve). A 21G needle was used to puncture the cecum (at the midpoint). A small amount of feces was squeezed out to ensure patency. The cecum was placed back into the abdominal cavity. The peritoneum and abdominal muscles were sutured together with 6-0 silk sutures, and the skin was sutured together with 4-0 silk sutures. 3. Postoperative management: Mice were resuscitated by subcutaneous injection of 1 mL of warm saline and analgesic with 0.05 mg / kg buprenorphine; the sham surgery group underwent only abdominal surgery, without ligation or puncture of the cecum; 4. Model validation: Preliminary experiments showed that 75% cecal ligation and puncture could cause mice to begin dying 20 hours after surgery, with a mortality rate of 60-70% after 7 days, which met the criteria for a severe sepsis model.

[0064] II. Construction of the sham model: The sham-operated group mice were constructed using a similar method to the aforementioned mouse sepsis model, but the cecum was not ligated or punctured; suturing was only performed after incising the skin, peritoneum, and abdominal muscles. III. Experimental Groups: 1. Sham surgery group 2. Model Group (CLP) IV. Testing Methods 1. Transcriptome Sequencing Analysis: Total RNA was extracted from mouse lung tissue using TRIzol® reagents (Magen). The total amount and purity of the extracted RNA were determined using a Nanodrop ND 2000 (Thermo Scientific, USA). mRNA was purified from 1 μg of total RNA using oligo (dT) magnetic beads and then fragmented. Subsequently, using the mRNA fragments as templates, the first strand of cDNA was synthesized using random primers and reverse transcriptase (RNase H), followed by the synthesis of the second strand of cDNA using DNA polymerase I, RNase H, buffer, and dNTPs. Adapter sequences were ligated into the synthesized double-stranded cDNA fragments for PCR amplification. The PCR products were purified, and library quality was assessed using an Agilent Bioanalyzer 4150. Finally, sequencing was performed using an Illumina Novaseq 6000 / MGISEQ T7 sequencing platform. The data generated by the platform were used for bioinformatics analysis. The raw data was first processed using a Perl script to obtain clean reads usable for subsequent analysis. The HISAT2 software (http: / / daehwankimlab.github.io / hisat2 / ) was used to align the clean reads with a reference genome to obtain mapped reads for further analysis. FeatureCounts (http: / / subread.sourceforge.net / ) was used to calculate the number of reads aligned to each gene, and the FPKM value for each gene was calculated based on its length. DESeq2 (http: / / bioconductor.org / packages / release / bioc / html / DESeq2.html) was used to perform differential gene expression analysis between groups. The default screening thresholds for differentially expressed genes were: |log2FC| > 1 and Padj < 0.05. A heatmap is used to display the expression of some differentially expressed genes.

[0065] 2. RT-qPCR validation: Total RNA was extracted using the TRIzol method (Invitrogen), reverse transcribed into cDNA using PrimeScript™ RT Master Mix (TaKaRa), and qPCR was performed using the SYBR Green method (Yeasen). GAPDH was used as an internal control, and the relative expression level was calculated using the 2⁻ΔΔCt method. Primer sequences are shown in Table 1.

[0066] 3. Western blot: Proteins were extracted using RIPA lysis buffer (containing protease / phosphatase inhibitors, Beyotime), electrophoresed by 12% SDS-PAGE, transferred to PVDF membranes (Millipore), blocked with 5% skim milk for 1 h, incubated with primary antibody at 4°C overnight, incubated with secondary antibody at room temperature for 1 h, developed by ECL (Pierce), and the gray values ​​of the bands were quantified using ImageJ (β-actin was used as an internal control); information on the primary antibody is shown in Table 2.

[0067] 4. Immunohistochemistry / immunofluorescence assay: Paraffin sections were dewaxed to water, EDTA antigen retrieval (pH 9.0, ZSGB-BIO), blocked with 1% goat serum for 90 min, incubated with primary antibody at 4°C overnight, incubated with fluorescent secondary antibody at room temperature for 90 min (immunofluorescence) or DAB staining (immunohistochemistry), nuclear staining with DAPI, photographed with a 3DHISTECH panoramic scanner or Zeiss AXI0 microscope, and quantified using ImageJ.

[0068] Table 1

[0069] Table 2

[0070] V. Test Results All experiments were independently repeated at least three times. Data are expressed as mean ± standard deviation (mean ± SD). GraphPad Prism 9.0 software was used for analysis. The t-test was used for comparisons between two groups, and one-way ANOVA or two-way ANOVA was used for comparisons among multiple groups. Tukey's method was used for multiple comparisons. p < 0.05 was considered statistically significant.

[0071] 1. Figure 1 A shows the transcriptome sequencing results of lung tissue from wild-type mice 12h and 24h after CLP surgery. The heatmap shows the expression of PDE family genes. As sepsis progresses (12h to 24h after CLP surgery), the expression of PDE4B in lung tissue is significantly upregulated, while the expression of other PDE subtypes (such as PDE4A, PDE4C, and PDE4D) is stable or decreased. 2. RT-qPCR validation results showed that 12 h after CLP surgery, the expression level of PDE4B mRNA was 5.0 times that of the sham-operated group (p < 0.0001); 24 h after surgery, it was 6.5 times that of the sham-operated group (p = 0.0006) (Figure 1B). 3. Western blot results showed that 12 hours after CLP, the expression level of PDE4B protein was 3.6 times that of the sham-operated group (p < 0.001); 24 hours after CLP, it was 4.3 times that of the sham-operated group (p < 0.0001) (Figure 1C). Figure 1 D).

[0072] 4. Immunohistochemical analysis showed that PDE4B was specifically highly expressed in vascular endothelial cells (CD31+) and infiltrating myeloid cells (MPO+) of lung tissue from septic mice (Figure 1E).

[0073] In summary, a multi-microbial induced sepsis model was established in mice via cecal ligation and puncture (CLP). Transcriptome sequencing of lung tissue from wild-type mice revealed that PDE4B expression was significantly upregulated with increasing sepsis severity, while the expression of other PDE subtypes remained stable or decreased. RT-qPCR and Western blot validation showed that 12 h after CLP, the expression level of PDE4B mRNA in lung tissue was 5.0-fold (p < 0.0001) and the protein expression level was 3.6-fold (p < 0.001) compared to the sham-operated group; 24 h after CLP, the mRNA expression level was 6.5-fold (p = 0.0006) and the protein expression level was 4.3-fold (p < 0.0001). Immunohistochemical results indicated that PDE4B was specifically and highly expressed in vascular endothelial cells (CD31+) and infiltrating myeloid cells (MPO+) in the lung tissue of sepsis-affected mice.

[0074] Example 2: Protective effect of PDE4B gene deletion against sepsis I. Animal source and breeding: PDE4B KO mice (PDE4B gene knockout mice, PDE4B- / -): 129 / Ola×C57BL / 6 background, backcrossed 10 times to C57BL / 6, purchased from Mutant Mouse Resource & Research Centers (Davis, CA).

[0075] Wild-type mice (C57BL / 6J, PDE4B gene-conserving mice, PDE4B+ / +) were purchased from Beijing Huafukang Biotechnology Co., Ltd., and are referred to as WT below. Housing conditions: SPF-grade animal room, temperature 22-25℃, humidity 50-60%, 12-hour light-dark cycle, free access to food and water; all experiments were approved by the Animal Ethics Committee of Fuwai Hospital, Chinese Academy of Medical Sciences.

[0076] II. Experimental Grouping: 1. Sham operation group: including PDE4B KO mouse (PDE4B- / -) group and WT mouse (PDE4B+ / +) group.

[0077] 2. Model group (CLP): including PDE4B KO mouse (PDE4B- / -) group and WT mouse (PDE4B+ / +) group.

[0078] III. Detection Methods: 1. Survival analysis: The survival status of mice was observed daily after surgery, and the 7-day survival rate was recorded. The survival curve was plotted using the Kaplan-Meier method, and the differences were analyzed using the Log-rank test.

[0079] 2. Lung injury assessment: 2.1 Wet-to-dry weight ratio: Lung tissue was taken 12 hours after surgery, weighed wet, dried at 55℃ for 24 hours, weighed dry, and the wet-to-dry weight ratio (wet weight / dry weight) was calculated.

[0080] 2.2 Vascular permeability test (Evans blue method): 12 h postoperatively, mice were injected with 30 mg / kg Evans blue (3% concentration, Sigma) via the tail vein. 30 min later, the mice were sacrificed, and the left ventricle was perfused with citrate buffer (pH 4.0). Lung tissue was collected, dried, and weighed. It was extracted with 1 mL of formamide at 55 °C for 24 h, centrifuged at 2000 g for 20 min, and the supernatant was collected. The absorbance was measured at 620 nm, and the Evans blue content (μg / mg tissue) was calculated according to the standard curve.

[0081] 2.3 Histopathology: Lung tissue was fixed in 4% paraformaldehyde, embedded in paraffin and sectioned (5μm), stained with HE, and the alveolar septum thickness was measured using ImageJ software (18 fields of view were randomly selected from each mouse, and 6 alveoli were measured in each field of view); MPO immunofluorescence staining (primary antibody: Abcam ab208670, 1:100) was performed, and the proportion of MPO positive area to DAPI positive area was calculated.

[0082] 3. Microcirculation monitoring: 12 hours postoperatively, intraperitoneal anesthesia with 80 mg / kg sodium pentobarbital was administered, and hair was removed from the chest and hind limbs. The temperature was maintained at 37°C, and blood perfusion (PU value) of the heart and hind limb skin was continuously monitored for 5 minutes using a PeriCam PSI System (Perimed).

[0083] 4. Cardiac function test: 24 hours after CLP, mice were anesthetized and their short-axis heart was scanned using a VisualSonics Vevo 2100 ultrasound system (MS400 probe). Heart rate was recorded, and LVEF (left ventricular ejection fraction), LVEDV (left ventricular end-diastolic volume), and LVESV (left ventricular end-systolic volume) were measured by M-mode ultrasound. Stroke volume (SV=LVEDV-LVESV) and cardiac output (CO=SV×heart rate) were calculated.

[0084] 5. Biochemical and inflammatory factor detection: Blood was drawn from the inferior vena cava 12 hours postoperatively, and plasma was separated by centrifugation at 8000 rpm for 5 min. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CRE), and blood urea nitrogen (BUN) were detected using a fully automated biochemical analyzer (FUJIFILM). Tumor necrosis factor-α (TNF-α, Elabscience E-EL-M3063) and interleukin-1β (IL-1β, Elabscience E-MSEL-M0003) were detected using an ELISA kit, following the instructions.

[0085] IV. Test Results 1. Improved survival: The 7-day survival rate of PDE4B KO mice increased from 26% in WT mice to 65% (p<0.05). The survival curves showed significant separation at 24 hours post-surgery, suggesting that PDE4B plays a key role in the early pathological process of sepsis (Figure 2A).

[0086] 2. Relief of lung injury: 2.1 Lung wet-to-dry weight ratio (reflecting pulmonary edema): 4.718±0.044 in WT mice and 4.262±0.182 in PDE4B KO mice (p<0.0001) (Figure 2B).

[0087] 2.2 Vascular permeability (Evans blue method): The Evans blue content in the lung tissue of WT mice was 0.690±0.155 μg / mg tissue, while it decreased to 0.285±0.057 μg / mg tissue in PDE4B KO mice (p<0.0001) (Figure 2C).

[0088] 2.3 Histopathology: The alveolar septa of WT mice were significantly thickened (7.677±1.037 μm), while the alveolar septa thickness of PDE4B KO mice decreased to 3.373±0.441 μm (p<0.0001) (Figure 2D). Figure 2 E); Myeloid cell infiltration (MPO positive area) decreased from 26.263%±5.125 to 15.259%±3.084 (p<0.001) (Figure 2F, Figure 2G).

[0089] 3. Microcirculation recovery: Laser Doppler detection showed that 12 hours after CLP, cardiac blood perfusion in PDE4B KO mice recovered from 602.899±111.675 PU in WT mice to 785.274±53.120 PU (p=0.0002), and hind limb blood perfusion recovered from 49.485±16.240 PU to 88.509±7.631 PU (p<0.0001) (Figures 2H-2J).

[0090] 4. Cardiac function protection: Echocardiography showed that WT mice exhibited significant systolic dysfunction (decreased left ventricular ejection fraction) and impaired cardiac pumping function (decreased cardiac output) 24 hours after CLP surgery, while PDE4B KO mice showed significant preservation of cardiac function (Figure 2K). Figure 2 L).

[0091] 5. Liver and Kidney Function and Inflammation Suppression: 24 hours after CLP surgery, plasma ALT, AST, CRE, BUN, TNF-α, and IL-1β levels in WT mice were significantly elevated, indicating liver and kidney damage and inflammation. PDE4B gene knockout significantly reduced plasma ALT, AST, CRE, and BUN levels in mice (Figure 2M-). Figure 2 P), TNF-α and IL-1β concentrations decreased significantly (Figure 2Q, Figure 2 R).

[0092] Example 3: Validation of the therapeutic effect of PDE4B inhibitors The therapeutic effects of the non-selective PDE4 inhibitor roflumilast and the selective PDE4B inhibitor BR29175 in sepsis were verified.

[0093] Among them, the chemical structure of BR29175, a selective inhibitor of PDE4B, is as follows: The synthetic route is as follows:

[0094] Among them, compound A is Compound B is .

[0095] I. Construction of the mouse model 1. Construction of a mouse sepsis model: Same as Example 1.

[0096] 2. Construction of the sham surgery model: Same as Example 1.

[0097] II. Experimental Grouping: 1. Sham surgery group 2. Roflumilast group (CLP+Rof) 3. BR29175 group (CLP+29175) 4. Solvent group (CLP+Veh) III. Dosing Regimen Mice were given an intravenous injection of the drug (5 mg / kg) immediately after CLP surgery, followed by a subcutaneous injection of the same dose 8 hours later. The solvent group was injected with physiological saline containing the same volume of DMSO.

[0098] Specifically, mice were treated twice: the first dose of either rofluster (5 mg / kg) or BR29175 (5 mg / kg) or a solvent (containing an equal amount of DMSO as a cosolvent) was administered intravenously immediately after CLP, and the second dose was administered subcutaneously 8 hours after the procedure to maintain the drug concentration in the blood.

[0099] IV. Detection Methods: 1. Survival analysis: Same as Example 2.

[0100] 2. Clinical symptom assessment: The clinical manifestations of mice after CLP surgery were assessed using the following 6 indicators, each scored from 0 to 4 points, corresponding to 5 levels of symptom severity. The higher the score, the more severe the clinical symptoms.

[0101] (1) Hair erection status: 0 points - smooth hair; 1 point - a small amount of hair erection on the back; 2 - a large amount of hair erection on the back; 3 - edema in the mouse; 4 - weakness in the mouse.

[0102] (2) Degree of consciousness impairment: 0 points - mouse is active; 1 point - mouse is active but unwilling to stand; 2 points - activity is reduced but it can move freely; 3 points - activity is significantly reduced and it only moves after being provoked; 4 points - mouse is completely still. (3) Response to stimuli: 0 points - immediate response to sound and touch; 1 point - slow or no response to sound stimuli, immediate response to touch (moves to avoid touch); 2 points - slow or no response to sound stimuli, slight response to touch (moves a few steps); 3 points - slow or no response to sound stimuli, slow response to touch (does not move); 4 points - weak or no response to any stimulus, the mouse cannot stand up when pushed over. (4) Whether there is discharge from the corner of the eye: 0 points - eyes fully open; 1 point - eyes not fully open, with or without discharge; 2 points - eyes half closed, with or without discharge; 3 points - eyes more half closed, with or without discharge; 4 points - eyes fully closed or with milky white discharge. (5) Respiratory rate: 0 points - normal respiratory rate (>150 breaths / min); 1 point - slightly decreased respiratory rate (120-150 breaths / min); 2 points - moderately decreased respiratory rate (100-120 breaths / min); 3 points - significantly decreased respiratory rate (80-100 breaths / min); 4 points - extremely low respiratory rate (<80 breaths / min) (6) Breathing quality: 0 points - normal breathing without wheezing or difficulty; 1 point - occasional dyspnea; 2 points - dyspnea without wheezing; 3 points - dyspnea with wheezing; 4 points - wheezing 3. Evaluation of multi-organ protection effect: Same as in Example 2.

[0103] 4. Safety assessment: Mice were treated with solvent, roflufenicol, and BR29175 immediately after CLP, and their movements were recorded and filmed within 2 minutes.

[0104] Starting from the beginning of the video, one frame is extracted every 30 seconds, for a total of four frames. Figure 4 AD).

[0105] V. Test Results 1. Improved living conditions: The 7-day survival rates of the roflumilast group (CLP+Rof) and the BR29175 group (CLP+29175) were 58% and 61%, respectively, which were significantly higher than the 22% of the solvent group (CLP+Veh) (Figure 3A).

[0106] 2. Relief of clinical symptoms: The clinical symptom scores (MSS) of mice were continuously assessed over time to obtain the score curves. The area under the curve (AUC) of the score curves was calculated. The MSS of the roflumilast group (CLP+Rof; AUC=22.80) and the BR29175 group (CLP+29175; AUC=21.77) were significantly lower than those of the solvent group (CLP+Veh; AUC=43.82) (Figure 3B). Roflumilast and BR29175 significantly improved the symptoms of sepsis in mice.

[0107] 3. Multi-organ protection: Both roflumilast and BR29175 significantly reduced lung wet-to-dry weight ratio, vascular permeability, alveolar septal thickness, and MPO infiltration (Figure 3C-). Figure 3 G), restore blood perfusion to the heart and hind limb skin ( Figure 3 H, Figure 3I), improves cardiac contractile function and blood pumping function (Figure 3J, Figure 3 K), reduces the levels of liver and kidney function impairment markers (ALT, AST, CRE, BUN) and inflammatory factors (TNF-α, IL-1β) (Figure 3L- Figure 3 Q) 4. Safety Advantages: Roflumilast group mice (CLP+Rof, mouse 2) experienced significant adverse reactions post-surgery, primarily manifested as: lethargy, sluggish response to stimuli, rapid breathing, lethargy, transient drowsiness, half-closed eyes, or discharge. Sham-operated group mice (Sham, mouse 1), BR29175 group mice (CLP+29175, mouse 3), and solvent group mice (CLP+Veh, mouse 4) were active, moving freely at the bottom of their cages and exhibiting normal exploration, sniffing, and standing behaviors. While the BR29175 group (CLP+29175, mouse 3) showed comparable efficacy to the roflumilast group (CLP+Rof, mouse 2), it exhibited no significant side effects (e.g., no transient drowsiness or reduced activity), demonstrating superior safety. Figure 4 AD).

[0108] The above description is merely a specific implementation of this application. Those skilled in the art will clearly understand that, for the sake of convenience and brevity, the specific working process described above can be referred to the corresponding process in the foregoing method embodiments, and will not be repeated here. It should be understood that the protection scope of this application is not limited thereto. Any person skilled in the art can easily conceive of various equivalent modifications or substitutions within the technical scope disclosed in this application, and these modifications or substitutions should all be covered within the protection scope of this application.

Claims

1. The use of a class of compounds that target and inhibit PDE4B in the preparation of drugs for the prevention and / or treatment of sepsis.

2. The application according to claim 1, characterized in that, The compounds that target and inhibit PDE4B include selective PDE4B inhibitors.

3. The application according to claim 2, characterized in that, The selective PDE4B inhibitors include at least one of namisitol, BR compounds, compounds of formula I, compounds of formula II, compounds A2-A4, and compounds B2-B4; Among them, the chemical structure of BR-type compounds is as follows: , L is selected from a single bond or optionally from a C1-C3 alkylene group substituted with one or more substituents selected from -D, halogen, C1-C3 alkyl, or C1-C3 alkoxy; R1 is selected from -D, -H, halogen, -OH, -CN, -CHO, -OR5, -OC(O)R5, -COOR5, -NR6R7, -CONR6R7, -SR5, -SOR5, -SO2NR6R7, -CH=NOR8, or R5 is independently selected from -D, -H, C1-C 15 Alkyl or benzo[a]heterocyclic group, wherein C1-C 15 Alkyl or benzo[a]heterocyclic group may be optionally surrounded by one or more groups selected from -D, halogen, -OH, -NH2, C1-C5 alkyl, , The substituents of R6 and R7 are each independently selected from -D, -H, -OH, -CN, C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5 alkyl, wherein the C1-C5 alkyl or C1-C5 alkoxy or 3-6 membered cycloalkyl or -SO2-C1-C5 alkyl is optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, C1-C5 alkoxy, or R6 and R7 are connected together with the N atom to which they are attached to form a 3-10 membered heterocyclic alkyl, wherein the 3-10 membered heterocyclic alkyl is optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo (=O), C1-C6 alkyl, C1-C6 alkoxy or hydroxyl-substituted C1-C6 alkyl, and R8 is selected from -D, -H or -COR5; R2 is selected from 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl, or 5-10-membered heteroaryl, wherein the 3-10-membered cycloalkyl, 3-10-membered heterocycloalkyl, C6-C 10 The aryl group, or 5-10 heteroaryl group, is optionally substituted by one or more substituents selected from -D, halogen, -OH, -NH2, -CN, oxo, C1-C5 alkyl, C2-C5 alkenyl, C1-C5 alkoxy, hydroxy-substituted C1-C5 alkyl, C1-C3 alkyl-O-C1-C3 alkyl, -CO-C1-C5 alkyl, -CONR6R7, C1-C5 haloalkyl, C2-C5 haloalkenyl, C1-C5 haloalkoxy, hydroxy-substituted C1-C5 haloalkyl, C1-C3 haloalkyl-O-C1-C3 haloalkyl or -CO-C1-C5 haloalkyl; R3 and R4 are independently selected from -D, -H, halogen, -OH or C1-C6 alkyl, X is selected from -O-, -S-, -SO-, -SO2- or -CO-, Y is selected from -CH2- or -NR6-, and n is 0 or 1; The chemical structure of compound I is X is selected from O, S and NR. 7 ;R 1 R 2 R 4 R 5 R 7 R 9 and R 10 Independently selected from hydrogen, acyl, optionally substituted low-carbon alkyl, optionally substituted low-carbon alkenyl, optionally substituted low-carbon ynyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaryl. However, the condition is R 1 and R 2 、or R 4 and R 5 、or R 9 and R 10 、or R 2 and R 3 They can combine to form optionally substituted heterocycles; R 3 Selected from cyano, nitro, -C(Z)R 8 S(O2)NR 9 R 10 -S(O2)R 11 and optionally substituted low-carbon alkyl groups; Y and Z are independently selected from O and S; R 6 and R 8 Selected from hydroxyl, alkoxy, thioalkoxy, optionally substituted amine, optionally substituted low carbon alkyl, optionally substituted low carbon alkenyl, optionally substituted low carbon alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl and optionally substituted heterocycle; and R 11 Independently selected from hydroxyl, alkoxy, thioalkoxy, optionally substituted low carbon alkyl, optionally substituted low carbon alkenyl, optionally substituted low carbon alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl and optionally substituted heteroaryl; and their salts, prodrugs and isomers; The chemical structure of compound II is as follows: Ring A is a 5-10 membered aromatic ring or heteroaromatic ring; B is selected from 3-10 membered heterocyclic alkyl, 3-10 membered heterocyclic alkenyl, or 3-10 membered cycloalkyl; R a and R b Each group is independently selected from H, halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, and C. 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 alkyl carbonyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, 3- to 10-membered heterocyclic alkyl; the C 1-6 Alkyl, C 3-8 cycloalkyl, C 1-6 Deuterated alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-8 Halogenated cycloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 alkyl carbonyl, C 1-6 Alkoxy and C 1-6 The haloalkoxy group is optionally surrounded by one or more R c Replace; the R c Substituents selected from the following: halogen, hydroxyl, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkyl hydroxyl, C 1-6 alkyl carbonyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; when the substituent R c When there are multiple R, the R c Same or different; m and n are 0, 1, 2 or 3 respectively; Y is selected from NR 1 O, S or CHR 1 ; R 1 Selected from H, C 1-10 Alkyl, C 2-6 alkenyl, the C 1-10 Alkyl, C 2-6 Alkenyl groups are optionally separated by one or more R groups d Replace; the R d Substituents selected from the following: halogen, C 1-3 Fluoroalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -COO-C 1-6 Alkyl, -C(O)NR f R f 5-8 Yuanfanghuan, -het 1 Single or double ring-C 5-8 -cycloalkyl; wherein, the R f For hydrogen, C 1-6 Alkyl; the het 1 This refers to a 5-8 member monocyclic or bicyclic, saturated or unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, S, and O. Compounds A2 to A4 include ; Compounds B2-B4 include .

4. The application according to claim 1, characterized in that, The compounds that target and inhibit PDE4B include at least one of siRNA, sgRNA, dsRNA, shRNA, miRNA, antisense nucleic acid, antibody, and enzyme that target PDE4B.

5. The application according to claim 1, characterized in that, The compound that targets and inhibits PDE4B satisfies at least one of the following conditions: (1) It can inhibit PDE4B enzyme activity; (2) It can reduce the content of PDE4B enzyme.

6. The application according to claim 1, characterized in that, The sepsis includes at least one of bacterial sepsis, fungal sepsis, and viral sepsis.

7. The application according to claim 1, characterized in that, The sepsis includes functional damage to organs, including at least one of sepsis-induced lung injury, myocardial dysfunction, liver injury, kidney injury, and microcirculatory disturbance.

8. The application according to claim 1, characterized in that, The prevention and / or treatment of sepsis includes at least one of the following: reducing the lung wet-to-dry weight ratio, improving vascular permeability, reducing alveolar septal thickness, reducing myeloid cell infiltration area, restoring cardiac and hindlimb blood perfusion, improving cardiac systolic function, improving cardiac diastolic function, reducing the expression of liver and kidney function damage markers, and reducing the expression level of inflammatory factors.

9. The application according to claim 1, characterized in that, The drug may also include pharmaceutically acceptable carriers, excipients, or salts; and / or, The drug contains 0.01%-99.5% by weight of the compound that targets and inhibits PDE4B.

10. The application according to claim 1, characterized in that, The dosage form of the drug includes a gastrointestinal dosage form or a non-gastrointestinal dosage form; preferably, the route of administration of the drug includes a gastrointestinal route or a non-gastrointestinal route.

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