CN-122005553-A - Application of gaboxadol or pharmaceutically acceptable salt thereof in preparation of medicine for treating liver fibrosis diseases

Abstract

The invention discloses application of gaboxadol or pharmaceutically acceptable salt thereof in preparing medicines for treating liver fibrosis diseases, belongs to the technical field of biological medicines, and researches show that the compound can influence collagen fiber crosslinking by targeted inhibition of prolyl-4-hydroxylase a1 (prolyl-4-hydroxylase alpha 1, P4ha 1) function, thereby playing an anti-fibrosis role. In a carbon tetrachloride-induced mouse liver fibrosis model, intraperitoneal injection of gaboxadol hydrochloride can remarkably reduce the hydroxyproline content and collagen deposition in liver type I collagen molecules and reduce liver hardness. The surface plasmon resonance experiment proves that the fluorescent dye has specific binding capacity with P4ha 1. Toxicity experiments show that the medicine has good safety at effective doses. The invention provides new drug candidates and theoretical basis for liver fibrosis treatment.

Inventors

• YANG LE
• LI LIYING
• WU MEIZHEN
• TAN QIONG
• MAO QITAO

Assignees

• 首都医科大学

Dates

Publication Date

20260512

Application Date

20260326

Claims (9)

1. 1. Use of gaboxadol or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of liver fibrosis.
2. 2. The use of gaboxadol or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for treating liver fibrosis diseases, wherein the pharmaceutically acceptable salt of gaboxadol is gaboxadol hydrochloride having the following structural formula: 。
3. 3. the use of gaboxadol or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for the treatment of liver fibrosis diseases wherein the medicament acts as an anti-fibrotic agent by targeted inhibition of prolyl-4-hydroxylase a1 function to affect collagen fibre cross-linking.
4. 4. Use of gaboxadol or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for the treatment of liver fibrosis diseases, wherein the route of administration of the medicament comprises intraperitoneal injection.
5. 5. Use of gaboxadol or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for the treatment of liver fibrosis diseases wherein the medicament is administered in an amount of 0.75 to 3 mg per kg body weight.
6. 6. The use of gaboxadol or a pharmaceutically acceptable salt thereof according to claim 5, in the manufacture of a medicament for treating a liver fibrosis disease, wherein the medicament is administered in an amount of 0.75 mg/kg, 1.5 mg/kg or 3 mg/kg body weight.
7. 7. Use of gaboxadol or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for the treatment of liver fibrosis diseases, wherein the medicament comprises a pharmaceutically acceptable excipient, carrier or adjuvant in addition to the active ingredient.
8. 8. The use of gaboxadol or a pharmaceutically acceptable salt thereof according to claim 7 in the manufacture of a medicament for the treatment of liver fibrosis diseases, wherein the dosage form of the medicament comprises an injection, tablet, capsule or sustained release formulation.
9. 9. The use of gaboxadol or a pharmaceutically acceptable salt thereof according to claim 8 in the manufacture of a medicament for the treatment of liver fibrosis diseases, wherein the medicament is in the form of an injection.

Description

Application of gaboxadol or pharmaceutically acceptable salt thereof in preparation of medicine for treating liver fibrosis diseases Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to application of gaboxadol or pharmaceutically acceptable salt thereof in preparation of a medicine for treating liver fibrosis diseases. Background Abnormal synthesis and cross-linking of collagen molecules, which are a spiral structure with extremely high tensile strength formed by intertwining three peptide chains with glycine-X-Y repeats, are the ‌ core pathological feature ‌ of fibrotic diseases (such as liver fibrosis). Wherein the hydroxylation modification of the proline residue at the "Y" site is critical for the stability of the triple helix structure of the collagen molecule and for crosslinking to form a functional collagen fiber. Prolyl-4-hydroxylase a1 (prolyl-4-hydroxylase alpha 1, P4ha 1) is a key collagen modifying enzyme responsible for this process, which hydroxylates the proline at the "Y" site of the glycine-X-Y repeat of collagen to form 4-hydroxyproline, reinforcing the cross-links between collagen fibers, further enhancing tissue stiffness, thereby exacerbating the progression of liver fibrosis. No specific inhibitor targeting P4ha1 exists at present, and the short plate limits the promotion and clinical transformation application of related researches. Based on the background, the development of the small molecular medicine for targeted inhibition of the P4ha1 function has important clinical application value, is hopeful to become an effective strategy and a force direction for reversing liver fibrosis, and also provides a certain reference for fibrosis treatment of other organs. Although a plurality of medicines with anti-hepatic fibrosis curative effects are currently in clinical researches, most of the medicines have toxic and side effects, and cannot reach the end point of clinical experiments, for example, potential anti-hepatic fibrosis candidate medicines which are once paid attention by the industry, including Selonsertib, simtuzumab, emricasan, elafibranor, obeticholic acid, ALDAFERMIN, SELADELPAR, EDP-305, cenicriviroc and the like, are all disfavored in clinical development of hepatic fibrosis caused by metabolism-related steatohepatitis (metabolic dysfunction-associated steatohepatitis, MASH) due to multiple reasons such as the fact that the curative effects are not at the end point, safety problems or poor benefit-risk ratio. Remmetilobal (Resmetirom, trade name Rezdiffra), a selective thyroid hormone receptor-beta (THR-beta) agonist, was approved by the FDA on day 14 of 3, 2024, for use in the treatment of non-cirrhosis MASH adult patients with intermediate and late liver fibrosis (stages F2-F3), a treatment drug in the MASH field of the first worldwide. However, no drugs directed to the "collagen fiber cross-linking" core link of liver fibrosis have been marketed so far. Therefore, the development of a new anti-liver fibrosis drug based on the 'targeted inhibition of P4ha1 function to influence collagen fiber crosslinking' has important research significance and application value. Gaboxadol hydrochloride (Gaboxadol hydrochloride), chemical formula C 6H9ClN2O2, is a potent agentAminobutyric acid type a receptor (GABA A receptor) agonists and methods of useAminobutyric acid type C receptor (GABA C receptor) antagonists are used as tool compounds in neuroscience research. GABA A receptor is widely distributed in brain and is the main inhibitory receptor, and after activation, it is proved in animal model that it can inhibit neuron discharge, maintain neural network excitation-inhibition balance, and play roles in regulating anxiety, sedation, memory and motor control (rat, 5,6,15 mg/kg body weight). GABA C receptor is mainly present in the ‌ retina, whose main function is to regulate visual signal processing (e.g. contrast, light adaptation), affecting visual perception, and is very low expressed in the central nervous system, ‌ is not found to be involved in sedative effects in the gaboxadol hydrochloride actuator hypnotic model. Gaboxadol hydrochloride was advanced by the united states biopharmaceutical company Ovid Therapeutics as phase ‌ clinical drug ‌, with the aim of ameliorating sleep disorders associated with angel's syndrome (Angelman Syndrome), a rare neurological disorder, but not expected in phase III clinical trials, and was not approved for the treatment of insomnia in humans. Thus, current studies on gaboxadol hydrochloride remain in the laboratory stage and have not been approved as a clinical drug. The prior literature report does not disclose any report on gaboxadol or a salt thereof to alleviate liver fibrosis. Disclosure of Invention Aiming at the technical problems, the invention provides application of gaboxadol or pharmaceutically acceptable salt thereof in preparing medicaments for treating liver fibrosis