CN-121987629-A - Use of PLD2 inhibitor in preparing medicine for targeted inhibition of NLRP3 inflammation small body activation

Abstract

The invention discloses an application of PLD2 inhibitor in preparing a drug for targeted inhibition of NLRP3 inflammation small body activation, and belongs to the technical field of pharmaceutical chemistry. The invention discovers that VU0364739 and pharmaceutically acceptable derivatives thereof can efficiently, selectively and widely inhibit the activation of NLRP3 inflammatory bodies, and have good pharmacological effects in-vitro and in-vivo experiments, thereby providing reliable experimental basis and technical basis for preparing the medicines for treating NLRP3 inflammatory body Guan Yanzheng diseases.

Inventors

• Lin hualong
• LAN HUI

Assignees

• 中国人民解放军空军军医大学

Dates

Publication Date

20260508

Application Date

20260312

Claims (9)

1. Use of a pld2 inhibitor in the manufacture of a medicament for targeted inhibition of NLRP3 inflammatory body activation.
2. 2. The use according to claim 1, wherein the PLD2 inhibitor is VU0364739 or a derivative, isomer thereof.
3. 3. The use according to claim 2, wherein the PLD2 inhibitor inhibits NLRP3 inflammatory body activation by reducing maturation and release of IL-1 β and IL-18 and inhibiting self-shear activation of caspase-1.
4. 4. A pharmaceutical composition comprising VU0364739 or a derivative, isomer, and pharmaceutically acceptable adjuvant thereof as claimed in claim 2.
5. 5. The pharmaceutical composition of claim 4, wherein the pharmaceutical composition is in the form of an injection, a tablet, a pill, a capsule, a solution, a powder, a microsphere formulation, or a sustained release formulation.
6. 6. Use of VU0364739 in claim 2 or a pharmaceutical composition as described in claim 4 or 5 in the preparation of a formulation for the treatment of a disorder caused by activation of NLRP3 inflammatory bodies.
7. 7. The use according to claim 6, wherein the inflammatory or immune-related disorder induced by activation of the NLRP3 inflammasome comprises arthritis, atherosclerosis, type II diabetes, alzheimer's disease, parkinson's disease, nonalcoholic fatty liver disease, alcoholic liver disease, hepatitis, systemic inflammation, kidney inflammatory disease, peritonitis, gout, obesity-related chronic inflammation, asthma, acute respiratory distress syndrome, depression-related inflammation, pneumonia, lung injury caused by asbestos exposure, silicosis, behcet's disease, myocardial injury, uv-induced skin inflammation, amyotrophic lateral sclerosis, familial autoinflammatory syndrome, cold porphyrin-related periodic syndrome, contact hypersensitivity and sepsis.
8. 8. The use according to claim 7, wherein the inflammatory or immune-related disorder induced by activation of the NLRP3 inflammatory bodies is sepsis.
9. 9. The use according to any one of claims 6 to 8, wherein the dosage form is an injection, a tablet, a pill, a capsule, a solution, a powder, a microsphere preparation or a sustained release preparation.

Description

Use of PLD2 inhibitor in preparing medicine for targeted inhibition of NLRP3 inflammation small body activation Technical Field The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to application of a PLD2 inhibitor in preparing a drug for targeted inhibition of NLRP3 inflammatory body activation. Background NLRP3 (NOD-like receptor pyrin domain-containing protein) is a pattern recognition molecule that localizes in the cytoplasm and plays a pivotal role in the body's inflammatory response to a variety of endogenous and exogenous stimuli. The protein is capable of sensing widely available danger signals, including microbial related stimuli and endogenous stress signals caused by cell damage or metabolic abnormalities. When stimulated, NLRP3 interacts with the cyclin NEK7 (NIMA-RELATED KINASE 7) and initiates downstream signaling events, causing the adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) to aggregate and recruit the pro-caspase-1, thereby forming a functionally active inflammatory small complex. The complex is established to activate caspase-1, further mediate mature release of inflammatory factors (IL-1 beta, IL-18, etc.) and inflammatory cell death process, and has important significance in maintaining host defense and immune homeostasis. However, sustained or excessive activation of NLRP3 inflammatory corpuscles has been shown to be closely associated with the development of a variety of inflammation-related diseases, such as arthritis, atherosclerosis, type II diabetes, alzheimer's disease, parkinson's disease, and nonalcoholic fatty liver disease. Pharmacological intervention against the NLRP3 inflammatory body activation process is therefore considered a potentially valuable therapeutic strategy for inflammation. Currently, a variety of IL-1β -targeted biological agents have been approved for the treatment of diseases associated with abnormal activation of NLRP3 inflammatory bodies, such as for the clinical treatment of cold porphyrin-related periodic syndromes (CAPS), as well as for the research and therapeutic exploration of other inflammatory body-mediated diseases. However, activation of NLRP3 inflammatory bodies not only leads to IL-1 β production, but also initiates inflammatory cell pyro-death processes and promotes the release of a variety of pro-inflammatory factors, including IL-18, which are commonly involved in the development and progression of the disease. In addition, the production of IL-1β is not entirely dependent on NLRP3 inflammatory bodies, but can also be induced by other inflammatory or non-inflammatory body pathways, and thus, a blocking strategy directed solely to IL-1β may affect the normal immune defenses of the body and increase the risk of infection. Based on the above considerations, direct inhibition of the activation process of NLRP3 inflammatory bodies is considered a more targeted and potentially better tolerated therapeutic strategy. However, intervention drugs that directly target the NLRP3 inflammatory body activation process remain clinically lacking. VU0364739 is a selective small molecule inhibitor of phospholipase D2 (PLD 2), wherein the name is N- {2- [1- (3-fluorophenyl) -4-oxo-1, 3, 8-triazaspiro [4.5] dec-8-yl ] ethyl } naphthalene-2-carboxamide, and the molecular formula is C 26H27FN4O2, and the chemical structural formula is shown in fig. 1A. The research shows that the compound has extremely high inhibitory activity on PLD2, has obvious selectivity relative to PLD1, and can effectively distinguish different signal paths mediated by PLD2 and PLD 1. Previous researches show that inhibiting PLD2 activity by using VU0364739 can obviously reduce proliferation capacity of human breast cancer cell line MDA-MB-231 and induce apoptosis, which suggests that the compound has definite biological activity. However, no published report has been made so far regarding the role of VU0364739 in inflammatory diseases, especially its relationship with NLRP3 inflammatory small-scale related pathological processes. Disclosure of Invention The invention aims to provide an application of PLD2 inhibitor in preparing medicines for targeted inhibition of NLRP3 inflammatory activation of small bodies, so as to solve the problems in the background art. In order to solve the technical problems, the invention is realized by the following technical scheme: The invention aims to provide the use of PLD2 inhibitors in the preparation of medicaments for targeted inhibition of NLRP3 inflammatory body activation. Studies show that the compound can effectively inhibit NLRP3 inflammatory corpuscle assembly and activation processes induced by exogenous or endogenous stimulus. Preferably, the stimulus that induces activation of NLRP3 inflammatory bodies includes, but is not limited to, ATP, microbial toxins, monosodium urate (MSU) crystals, bacterial Lipopolysaccharide (LPS), and other dangerous signal molecule