CN-122005573-A - Application of small molecular compound Z57346765 in preparation of psoriasis treatment drugs

Abstract

The invention belongs to the technical field of biological medicines, and discloses application of a small molecular compound Z57346765 and pharmaceutically acceptable salts thereof in preparation of a medicament for treating psoriasis. The Z57346765 and pharmaceutically acceptable salts thereof or the medicament exert psoriasis treatment effects by inhibiting the expression or activity of PGK 1. The pharmaceutically acceptable carrier or excipient is selected from one or more of DMSO, PEG-300, tween-80, physiological saline, vegetable oil, mannitol, starch, lactose, magnesium stearate and hypromellose.

Inventors

• HE CONGCONG
• YAN LIN
• GAO XINGHUA
• QI RUIQUN

Assignees

• 中国医科大学附属第一医院

Dates

Publication Date

20260512

Application Date

20260227

Claims (10)

1. 1. Application of small molecule compound Z57346765 and pharmaceutically acceptable salt thereof in preparation of medicaments for treating psoriasis, wherein the small molecule compound Z57346765 has a structural formula as follows: 。
2. 2. the use according to claim 1, wherein Z57346765 and pharmaceutically acceptable salts thereof or the medicament exert a psoriasis treatment effect by inhibiting the expression or activity of PGK 1.
3. 3. The use according to claim 1, wherein the medicament comprises an effective dose of small molecule compound Z57346765 and a pharmaceutically acceptable carrier or excipient.
4. 4. The use according to claim 3, wherein the pharmaceutically acceptable carrier or excipient is selected from one or more of DMSO, PEG-300, tween-80, physiological saline, vegetable oil, mannitol, starch, lactose, magnesium stearate, hypromellose.
5. 5. The use according to claim 1, wherein the medicament is in the form of a tablet, capsule, granule, pill, powder, paste, suspension, oral liquid or injection.
6. 6. The use according to claim 5, wherein the injection is an intradermal injection, a subcutaneous injection or an intravenous injection.
7. 7. Use according to claim 1, wherein the medicament is administered in a dose of 5-50 mg/kg/day, preferably 5mg/kg, 15mg/kg, 25mg/kg, 35mg/kg or 50mg/kg.
8. 8. The use according to claim 1, wherein the psoriasis comprises psoriasis vulgaris, psoriasis rubra, psoriasis arthrosis or psoriasis pustulosa.
9. 9. An intradermal injection for treating psoriasis, which is characterized in that, Comprises a small molecule compound Z57346765 or pharmaceutically acceptable salts, solvents and pharmaceutically acceptable auxiliary materials thereof; Preferably, the solvent comprises DMSO, PEG-300 and Tween-80, and the volume ratio of the DMSO to the PEG-300 to the Tween-80 is preferably 1:5:4, and the concentration of the small molecule compound Z57346765 or pharmaceutically acceptable salt thereof in the injection is 5-25mg/mL; wherein, the structural formula of the small molecule compound Z57346765 is as follows: 。
10. 10. A topical pharmaceutical composition for the treatment of psoriasis comprising an effective dose of a small molecule compound Z57346765 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable composite carrier, wherein the small molecule compound Z57346765 has the structural formula: 。

Description

Application of small molecular compound Z57346765 in preparation of psoriasis treatment drugs Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a novel application of a small molecular compound Z57346765, in particular to an application of the compound in psoriasis treatment and a psoriasis treatment medicine containing the compound. Background Psoriasis is a chronic and recurrent autoimmune skin disease, the pathogenesis of which is complex, and is closely related to various factors such as heredity, environment, immune disorder, metabolic abnormality and the like. The clinical manifestation is that the skin has scale erythema or plaque, and the pathological characteristics comprise excessive proliferation, abnormal differentiation and inflammatory cell infiltration of keratinocytes, and the pathological characteristics can affect the systems of joints, cardiovascular systems and the like when serious, so that the physical and mental health of patients are greatly endangered. Currently, the treatment methods for psoriasis mainly comprise topical drugs (such as glucocorticoids and vitamin D analogues), systemic therapeutic drugs (such as methotrexate), biological agents (such as anti-TNF-alpha and IL-17 antibodies) and the like. However, the existing treatment scheme has a plurality of defects that the glucocorticoid is easy to cause adverse reactions such as skin atrophy, pigmentation and the like after long-term use, the biological preparation is expensive, partial patients have poor response or recurrence risk, and most of treatments can only relieve symptoms and cannot fundamentally intervene in pathogenesis. Therefore, development of a novel therapeutic drug with strong targeting, stable curative effect and high safety has important clinical demands. PGK1 (phosphoglycerate kinase 1) is a key enzyme in the glycolytic pathway responsible for catalyzing the conversion of 1, 3-diphosphoglycerate to 3-phosphoglycerate, while generating ATP, playing a central role in cellular energy metabolism. The prior researches show that PGK1 is closely related to various diseases, can promote proliferation and metastasis of tumor cells, and is involved in pathological process regulation in ischemic diseases. In the field of autoimmune diseases, metabolic reprogramming of immune cells (such as glycolysis enhancement) has been proved to be closely related to disease occurrence and development, but the specific expression characteristics and action mechanisms of PGK1 in psoriasis have not been elucidated in the prior art, and inhibitors against PGK1 have not been found to be useful in psoriasis treatment. Psoriasis treatment is still a global problem, and the existing medicines have a plurality of limitations, so that a novel intervention scheme is urgently needed to break through clinical bottlenecks. Mild psoriasis mainly uses external corticosteroid, calcipotriol or a combination of the two, but the powerful corticosteroid is easy to cause adverse reactions such as subcutaneous lipoatrophy, adrenal suppression and the like, and cannot be used for long-term clinic. The methotrexate, cyclosporine and tretinoin oral medicine is suitable for moderately severe psoriasis which is difficult to control by external medicine, and adverse reaction is prominent, wherein the methotrexate has obvious hepatotoxicity and serious gastrointestinal reaction, the cyclosporine is effective on severe psoriasis, but is accompanied by serious nephrotoxicity, gastrointestinal discomfort, hirsutism and the like, the abamectin has definite teratogenicity, is forbidden to pregnant women and pregnant women, and can possibly cause skin dryness, dyslipidemia, transaminase rise and other symptoms. Biological agent targeted therapy brings breakthrough to psoriasis treatment, and agents selectively targeting IL-17, IL-23 and TNF-alpha pathways significantly innovate the treatment pattern. The TNF-alpha inhibitor has definite curative effect, but symptoms aggravate or new contradiction psoriasis can appear after a part of patients take the medicine, and the IL-17 inhibitor, namely the Bristolonizumab, is accompanied with higher incidence risk of oral candidiasis. Non-biological small molecule drugs such as JAK/TYK2 inhibitors and PDE-4 inhibitors have the limitations of high cost, poor accessibility, high treatment failure rate, insufficient long-term safety data and the like. The defects cause psoriasis treatment to be in bottleneck, adverse reaction frequently occurs and relapse after drug withdrawal becomes a core clinical pain point, and PGK1 is closely related with the pathogenesis of psoriasis, so that a key theoretical support is provided for developing a novel treatment scheme. PGK1 acts as a key rate-limiting enzyme in glycolysis, whose activity directly regulates cellular energy metabolism. The hyperglycolysis (Warburg effect) of keratinocytes and immune cells of psoriasis patients