CN-121991006-A - AER270 diagnosis and treatment prodrug with hypochlorous acid response characteristic, and preparation method and application thereof

Abstract

The invention belongs to the field of biological medicine, and discloses an AER270 diagnosis and treatment prodrug with hypochlorous acid response characteristic, a preparation method and application thereof, and the AER270 diagnosis and treatment prodrug has a structure shown in a general formula I: The invention is based on the core structure of Methylene Blue (MB), utilizes gamma-aminobutyric acid (GABA), gabapentin or aminopropanol as a connecting chain, and is coupled with an AQP4 inhibitor AER270 through ester bonds or ether bonds, thereby realizing HOCl specific activation and rupture release active molecules AER270 and GABA or gabapentin, enhancing the penetrability of blood brain barrier and the selective treatment of cerebral stroke focus, simultaneously releasing reduced methylene blue molecules, being capable of specifically lighting the cerebral stroke focus and realizing diagnosis and treatment integration.

Inventors

• LING YONG
• Ji Liujie
• ZHENG JIAXIN
• ZHU LINA
• LUO NINGNING
• LIU DONGWEI
• LIU XIAO
• SHEN ZIMING
• Xiong Minxuan
• QIAN XIAOYANG

Assignees

• 南通大学
• 南通大学启东海洋研究院

Dates

Publication Date

20260508

Application Date

20251231

Claims (10)

1. 1. An AER270 diagnosis and treatment prodrug with hypochlorous acid response characteristics, wherein the chemical structure of the AER270 diagnosis and treatment prodrug is shown as the following formula:
2. 2. an AER270 diagnosis and treatment prodrug with hypochlorous acid response characteristics, wherein the chemical structure of the AER270 diagnosis and treatment prodrug is shown as the following formula:
3. 3. An AER270 diagnosis and treatment prodrug with hypochlorous acid response characteristics, wherein the chemical structure of the AER270 diagnosis and treatment prodrug is shown as the following formula:
4. 4. a method for preparing the AER270 diagnostic prodrug according to claim 1 wherein the synthetic route of the preparation method is shown in the following formula: The preparation method comprises the following steps: S1, 3, 7-bis (dimethylamino) -10H-phenothiazine-10-carbonyl chloride and methyl gamma-aminobutyrate are subjected to room temperature overnight under the condition of organic base until the reaction is complete, and the compound 2 is obtained through column chromatography purification, wherein the organic base is triethylamine or N, N-diisopropylethylamine; S2, hydrolyzing the compound 2 in an aqueous methanol solution of NaOH to obtain 4- (3, 7-bis (dimethylamino) -10H-phenothiazine-10-formamido) butyric acid; S3.4- (3, 7-bis (dimethylamino) -10H-phenothiazine-10-formamido) butyric acid and aquaporin inhibitor AER270 are subjected to esterification reaction under the conditions of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 4-dimethylaminopyridine, and after the reaction is complete, the compound I 1 is obtained through column chromatography.
5. 5. A method for preparing the AER270 diagnostic prodrug according to claim 2 wherein the synthetic route of the preparation method is shown in the following formula: The preparation method comprises the following steps: S1, carrying out overnight reaction on the compound 1 and aminopropanol at room temperature under the condition of organic base, and purifying by column chromatography to obtain a compound 4, wherein the organic base is triethylamine or N, N-diisopropylethylamine; s2, carrying out etherification reaction on the compound 4 and an aquaporin inhibitor AER270 under the condition of diisopropyl azodicarboxylate and PPh 3 to obtain a compound I 2 .
6. 6. A method for preparing the AER270 diagnostic prodrug according to claim 3 wherein the synthetic route of the preparation method is shown in the following formula: The preparation method comprises the following steps: S1, carrying out overnight reaction on the compound 1 and gabapentin at room temperature under the condition of organic base, and purifying by column chromatography to obtain a compound 6, wherein the organic base is triethylamine or N, N-diisopropylethylamine; S2, carrying out esterification reaction on the compound 6 and an aquaporin inhibitor AER270 under the condition of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and 4-dimethylaminopyridine to obtain a compound I 3 .
7. 7. Use of an AER270 diagnostic prodrug according to any one of claims 1-3 for the preparation of a fluorescence imaging reagent targeting cerebral ischemic tissues and cells.
8. 8. Use of AER270 diagnostic prodrug according to any one of claims 1-3 for the preparation of a reagent for imaging diagnosis of ischemic stroke and/or cerebral ischemia reperfusion injury.
9. 9. Use of an AER270 diagnostic prodrug according to any one of claims 1-3 for the preparation of an AQP4 inhibitor targeting cerebral ischemic tissue.
10. 10. Use of AER270 diagnostic prodrug according to any one of claims 1-3 for the preparation of a medicament for the treatment of ischemic stroke and/or cerebral ischemia reperfusion injury.

Description

AER270 diagnosis and treatment prodrug with hypochlorous acid response characteristic, and preparation method and application thereof Technical Field The invention belongs to the field of biological medicine, and relates to an AER270 diagnosis and treatment prodrug with hypochlorous acid response characteristic, and a preparation method and application thereof. Background Neuroinflammation is a common pathological basis for a number of acute and chronic central nervous system diseases, including stroke, traumatic brain injury, alzheimer's disease, multiple sclerosis, and the like. After cerebral stroke (ischemic or hemorrhagic), the brain tissue often develops cytotoxic edema and angiogenic edema, resulting in increased intracranial pressure and further decreased cerebral blood flow, exacerbating nerve damage. Activated astrocytes and microglia produce active oxygen during neuroinflammation, where hypochlorous acid produced by myeloperoxidase catalysis is a key and highly oxidative effector molecule in the inflammatory microenvironment. Excessive hypochlorous acid not only causes damage to neurons, oligodendrocytes and the like, but also further amplifies inflammatory cascade, aggravating blood-brain barrier destruction and cerebral edema. In ischemic brain areas, myeloperoxidase-mediated production of high concentrations of hypochlorous acid (HClO) constitutes a specific pathological microenvironment. By taking advantage of this property, designing prodrugs that are specifically activated by HClO becomes an advanced targeting strategy. Aquaporin 4 (AQP 4) is the predominant aquaporin in the central nervous system, and is predominantly distributed in the terminal feet of astrocytes (the sites of contact with blood vessels), and plays a key role in the formation and regression of cerebral oedema. In neuroinflammatory and brain injury states, the expression and function of AQP4 are significantly disturbed, and the cytotoxic cerebral edema mediated by it is a key factor leading to worsening of the neurological function and poor prognosis of patients. Thus, inhibition of AQP4 function has become an important strategy for the treatment of the above mentioned neurological disorders by relief of cerebral oedema. The small molecule AQP4 inhibitor N- (3, 5-bis (trifluoromethyl) phenyl) -5-chloro-2-hydroxybenzoamide (AER-270) shows low or unstable BBB penetration rate in animal models, too fast metabolism rate in vivo and short half-life. Cerebral edema is a dynamic process that lasts for several days after cerebral stroke, requiring the drug to maintain a stable and effective concentration in the brain over a therapeutic window of time. At the same time, AQP4 has important functions in other organs of the whole body (such as kidney, eyes and gastrointestinal tract), and the inhibition of AQP4 (or AQP family members with similar structures) expressed by other organs of the whole body can generate serious side effects. Therefore, in order to reduce systemic toxicity and improve the therapeutic effect of cerebral apoplexy, it is necessary to develop a highly central nervous system targeting and selective diagnosis and treatment prodrug. Disclosure of Invention In view of the above, the invention provides an AER270 diagnosis and treatment prodrug with hypochlorous acid response characteristic, and a preparation method and application thereof, wherein the AER270 diagnosis and treatment prodrug can rapidly crack and release an AQP4 inhibitor AER270 in the presence of HClO, and simultaneously maintain fluorescence properties of MB, and the strategy ensures local high concentration of two active ingredients at a lesion site, and simultaneously reduces systemic exposure, thereby being expected to remarkably improve treatment effect and reduce side effects. The specific technical scheme of the invention is as follows: in a first aspect, the invention provides an AER270 diagnostic prodrug having hypochlorous acid response characteristics, the AER270 diagnostic prodrug having a structure according to formula I: When (when) When the AER270 diagnosis and treatment prodrug has the chemical structure shown in the following formula: When (when) When the AER270 diagnosis and treatment prodrug has the chemical structure shown in the following formula: When (when) When the AER270 diagnosis and treatment prodrug has the chemical structure shown in the following formula: In a second aspect, the invention provides a preparation method of the AER270 diagnosis and treatment prodrug, wherein the synthetic route of the preparation method is shown in the following formula: The preparation method comprises the following steps: s1, 3, 7-bis (dimethylamino) -10H-phenothiazine-10-carbonyl chloride (compound 1) and methyl gamma-aminobutyrate are subjected to overnight reaction at room temperature under the condition of organic base, and the compound 2 is obtained through column chromatography purification, wherein the organic base is triethylamine