Glucokinase activators for cognitive impairment and neurodegenerative diseases

Abstract

The use of glucokinase activators or their prodrugs, or their pharmaceutically acceptable salts, isotopes, crystalline forms, hydrates, solvates, diastereomers, or enantiomers, in order to prevent, mitigate, or treat cognitive impairment or neurodegenerative disease in subjects, or to delay the progression of cognitive impairment or neurodegenerative disease in subjects, or to reduce the risk of cognitive impairment or neurodegenerative disease in subjects.

Description

[Technical Field]

[0001] This disclosure claims priority to Chinese patent application CN202310662626.8, filed on 6 June 2023. That application is incorporated by reference in its entirety as part of this disclosure.

[0002] This disclosure relates to a glucokinase activator for cognitive impairment and neurodegenerative diseases. [Background technology]

[0003] Type 2 diabetes mellitus (T2DM) is the most common metabolic disease, and its incidence is increasing year by year, making it an urgent public health issue that needs to be addressed globally. Regarding secondary complications of T2DM, there is a growing number of studies linking T2DM to cognitive impairment (CI) and neurodegenerative diseases, but the underlying pathogenesis behind these secondary complications is still not fully understood. Many studies have shown that people with diabetes, especially those with T2DM, are at higher risk of developing Alzheimer's disease (AD) (AM Nazareth, Dementia & Neuropsychologia (2017); Jun; 11(2): 105-113; G. Coolay et al., Psychoneuroendocrinology. Psychoneuroendocrinology (2011); 36, 77-86). Some studies even refer to Alzheimer's disease as type 3 diabetes (T3DM) (Suzanne M. de la Monte et al., J Diabetes Sci Technol (2008);2(6):1101-1113; Huang J et al., Frontiers in Aging Neuroscience (2023);15:1130253).

[0004] Despite extensive research, no pharmacological therapies have been identified that can prevent, delay, or alter the course of cognitive impairment (CI) and neurodegenerative diseases. Therefore, improved pharmacological therapies are needed for patients with cognitive impairment and neurodegenerative diseases. [Overview of the Initiative]

[0005] The inventors have surprisingly found that administering a glucokinase activator (such as dolzagliatin) can prevent, alleviate, or treat cognitive impairment or neurodegenerative diseases, slow the progression of cognitive impairment or neurodegenerative diseases, and reduce the risk of developing cognitive impairment or neurodegenerative diseases. Furthermore, the inventors have surprisingly found that in animal models, dolzagliatin slows the progression of cognitive impairment or neurodegenerative diseases (such as mild cognitive impairment (MCI) and Alzheimer's disease) and reduces the risk of developing cognitive impairment-related diseases.

[0006] One of the objectives of this specification is to investigate the effects of glucokinase activators on preventing, mitigating, or treating cognitive impairment or neurodegenerative diseases in subjects, as well as on delaying the progression of cognitive impairment or neurodegenerative diseases and reducing the risk of developing them.

[0007] In one embodiment, the disclosure provides the use of glucokinase activators or their prodrugs, or pharmaceutically acceptable salts, prodrugs, isotope-labeled compounds, crystalline forms, hydrates, solvates, diastereomers, or enantiomers thereof, in the manufacture of pharmaceuticals for preventing, mitigating, or treating cognitive impairment or neurodegenerative disease in subjects, or for delaying the progression of cognitive impairment or neurodegenerative disease in subjects, or for reducing the risk of developing cognitive impairment or neurodegenerative disease in subjects.

[0008] In one embodiment, the disclosure provides the use of dolzagliatin or its prodrugs, or pharmaceutically acceptable salts, isotopes, crystalline forms, hydrates, solvates, diastereomers, or enantiomers thereof, in the manufacture of pharmaceuticals for preventing, mitigating, or treating cognitive impairment or neurodegenerative disease in subjects, or for delaying the progression of cognitive impairment or neurodegenerative disease in subjects, or for reducing the risk of developing cognitive impairment or neurodegenerative disease in subjects.

[0009] In one embodiment, the disclosure provides the use of dolzagliatin or its prodrugs in the manufacture of a pharmaceutical product for preventing, mitigating, or treating cognitive impairment or neurodegenerative disease in a subject, or for delaying the progression of cognitive impairment or neurodegenerative disease in a subject, or for reducing the risk of developing cognitive impairment or neurodegenerative disease in a subject.

[0010] In another embodiment, the Disclosure provides a method for preventing, mitigating, or treating cognitive impairment or neurodegenerative disease, or for delaying the progression of cognitive impairment or neurodegenerative disease, or for reducing the risk of developing cognitive impairment or neurodegenerative disease, comprising administering a glucokinase activator or a prodrug thereof, or a pharmaceutically acceptable salt, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer thereof, to a subject in need.

[0011] In another embodiment, the Disclosure provides a method for preventing, mitigating, or treating cognitive impairment or neurodegenerative disease, or for delaying the progression of cognitive impairment or neurodegenerative disease, or for reducing the risk of developing cognitive impairment or neurodegenerative disease, comprising administering dolzagliatin or its prodrug, or a pharmaceutically acceptable salt, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer thereof to a subject in need.

[0012] In another embodiment, the Disclosure provides a method for preventing, mitigating, or treating cognitive impairment or neurodegenerative disease, or for delaying the progression of cognitive impairment or neurodegenerative disease, or for reducing the risk of developing cognitive impairment or neurodegenerative disease, comprising administering dolzagliatin or a prodrug thereof to a subject in need.

[0013] In another embodiment, the Disclosure provides glucokinase activators or prodrugs thereof, or pharmaceutically acceptable salts, isotopes, crystalline forms, hydrates, solvates, diastereomers, or enantiomers thereof, for use in preventing, mitigating, or treating cognitive impairment or neurodegenerative disease, or delaying the progression of cognitive impairment or neurodegenerative disease, or reducing the risk of developing cognitive impairment or neurodegenerative disease.

[0014] In another embodiment, the Disclosure provides dolzagliatin or its prodrugs, or pharmaceutically acceptable salts, isotopes, crystalline forms, hydrates, solvates, diastereomers, or enantiomers thereof, for use in preventing, mitigating, or treating cognitive impairment or neurodegenerative disease, or delaying the progression of cognitive impairment or neurodegenerative disease, or reducing the risk of developing cognitive impairment or neurodegenerative disease.

[0015] In another embodiment, the Disclosure provides dolzagliatin or a prodrug for use in preventing, mitigating, or treating cognitive impairment or neurodegenerative disease, or in delaying the progression of cognitive impairment or neurodegenerative disease, or in reducing the risk of developing cognitive impairment or neurodegenerative disease.

[0016] Another purpose of this disclosure is to investigate the effects of glucokinase activators (dolzagliatin, dolzagliatin prodrugs, etc.) on preventing, mitigating, or treating cognitive impairment or neurodegenerative disease in subjects, as well as on delaying the progression of cognitive impairment or neurodegenerative disease and reducing the risk of developing it. Subjects have one or more signs selected from type 1 diabetes, type 2 diabetes, early-onset adult-onset diabetes mellitus (MODY), gestational diabetes, impaired glucose tolerance, abnormal fasting blood glucose levels, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, cardiovascular disease, insulin resistance, and / or metabolic syndrome. [Modes for carrying out the invention]

[0017] definition

[0018] Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art in the field to which this disclosure pertains. In the event of any conflict, the definitions herein shall prevail.

[0019] In the specification and claims, the singular forms "a," "an," and "the (said)" include the plural form unless otherwise specified in the context.

[0020] All numerical values ​​or expressions relating to the quantities of components used in the specification and claims should be understood to be modified in all cases with “approximately.” When referring to a quantity or numerical range, the term “approximately” means that the quantity or numerical range is an approximation within the experimental variable (or within the statistical experimental error). Therefore, the quantity or numerical range may vary, for example, within ±5% of the quantity or numerical range.

[0021] As used herein and in the claims, “and / or” should be interpreted as meaning “either or both” of the relevant elements; that is, these elements may exist together or individually. Similarly, any multiple elements listed with “and / or” should be interpreted as “one or more” of the relevant elements. In addition to the elements specifically identified in the “and / or” clause, other elements relating to or unrelated to these specifically identified elements may be present as needed. Therefore, as a non-limiting example, when the statement “A and / or B” is used in combination with an open-ended expression such as “comprising,” it may refer to A only in one embodiment (which may include elements other than B), B only in another embodiment (which may include elements other than A), and both A and B in yet another embodiment (which may include other elements), and so on.

[0022] The abbreviations used in this disclosure have their common meanings in the fields of chemistry, biology, and pharmaceuticals.

[0023] "Pharmacologically usable" or "pharmaceutically acceptable" means that a substance is not biologically or otherwise undesirable. That is, the substance can be administered to an individual without causing undesirable biological effects or harmful interactions with other components of a composition containing the substance.

[0024] The term "pharmaceutically acceptable salt" refers to a salt that does not cause significant irritation to living organisms and retains the biological activity and properties of the compound.

[0025] The term "pharmaceutically acceptable carrier" refers to an inert component that does not cause significant irritation to the organism and does not impair the biological activity and properties of the administered compound. In this specification, "carrier" and "excipient" have the same meaning.

[0026] The term "therapeutic dose" refers to the amount of a drug that produces a desired biological outcome. This outcome may include a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or other desired changes in a biological system. For example, in therapeutic use, "therapeutic dose" refers to the amount of a composition containing the compounds disclosed herein as active ingredients required to clinically and significantly alleviate a disease. In individual cases, the appropriate "therapeutic dose" can be determined by a person skilled in the art through ordinary testing. Therefore, the expression "therapeutic dose" generally refers to the amount of an active substance that has a therapeutic effect.

[0027] The term "cognitive impairment" refers to a disorder in which animals exhibit a decline in cognitive functions or areas such as working memory, attention and arousal, language learning and memory, visual learning and memory, reasoning and problem-solving (executive functions, etc.), task processing speed, and / or social cognition. In particular, cognitive impairment is known to manifest as attention deficit, disorganized thinking, delayed thinking, difficulty in comprehension, attention deficit, loss of problem-solving ability, memory confusion, difficulty in expressing thoughts and / or integrating thoughts, feelings, and actions, and difficulty in excluding inappropriate thoughts, and can be used interchangeably with terms such as "cognitive deficit" and "cognitive damage." Symptoms of cognitive impairment include decreased attention, decreased language ability, decreased spatial and temporal awareness, decreased reasoning ability, or decreased judgment.

[0028] The terms “treat,” “prevent,” and “alleviate” are intended to mean slowing the progression of a disease, preventing the progression of a disease, and / or reducing the severity of symptoms that develop or are expected to develop. Specifically, “prevention” refers to reducing or eliminating the likelihood of contracting a disease, “alleviation” refers to reducing all or part of a disease and / or its associated symptoms, and “treatment” refers to eliminating all or part of a disease and / or its associated symptoms. Thus, these terms include improving existing disease symptoms, preventing additional symptoms, improving or preventing the underlying metabolic causes of symptoms, suppressing a disorder or disease, such as preventing the onset of a disorder or disease, mitigating a disorder or disease, inducing regression of a disorder or disease, alleviating a condition caused by a disease or disorder, or stopping the symptoms of a disease or disorder.

[0029] The term "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, all organisms belonging to the class Mammalia, namely humans, apes such as chimpanzees and other primates, and other non-human primates such as monkeys; domestic animals such as cattle, horses, sheep, goats, and pigs; pet animals such as rabbits, dogs, and cats; and laboratory animals such as rodents such as rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds and fish. In one embodiment of this disclosure, the mammal is a human being. The term "subject" includes patients with a confirmed diagnosis, but "subjects" do not need to have a special status (patient with a confirmed diagnosis, research participant, etc.) with respect to a hospital, clinic, or research facility.

[0030] It should be understood that the terms used herein are intended to describe specific embodiments and are not intended to limit them. Furthermore, while similar or equivalent methods, apparatus, and materials may be used to carry out or test this disclosure, alternative methods, apparatus, and materials are described below. [Brief explanation of the drawing]

[0031] [Figure 1] This study compares fasting blood glucose levels at weeks 6, 8, 12, 16, 20, 29, and 31 in the Wistar rat-solvent group, the GK rat-solvent group, and the GK rat-dolzagliatin group.

[0032] In the figure, the comparison between the GK rat-solvent group and the Wistar rat-solvent group showed *P<0.05, ***P<0.001, and ****P<0.0001, while the comparison between the GK rat-dorzagliatin group and the GK rat-solvent group showed #P<0.05 and ##P<0.01.

[0033] [Figure 2]This shows the mean time spent in the original platform quadrant during the Morris water maze spatial memory test conducted on Wistar rats-solvent group, GK rats-solvent group, and GK rats-dolzagliatin group.

[0034] In the figure, the comparison between the GK rat-solvent group and the Wistar rat-solvent group showed **P<0.01**, and the comparison between the GK rat-dolzagliatin group and the GK rat-solvent group showed #P<0.05.

[0035] [Figure 3] This shows the average distance traveled in the original platform quadrant during the Morris water maze spatial memory test conducted on Wistar rats-solvent, GK rats-solvent, and GK rats-dolzagliatin.

[0036] In the figure, the comparison between the GK rat-solvent group and the Wistar rat-solvent group showed **P<0.01**, and the comparison between the GK rat-dolzagliatin group and the GK rat-solvent group showed ##P<0.01**.

[0037] [Figure 4] Western blot bands are shown for two insulin receptor isoforms (IR-A protein and IR-B protein) and their corresponding internal reference protein GAPDH in the hippocampus of GK rats in the solvent group and the GK rat dolzagliatin group.

[0038] [Figure 5] Figure 4 shows the results of the statistical analysis of the normalized grayscale values ​​of the IR-A protein band. In the figure, the comparison between the GK rat-dolzagliatin group and the GK rat-solvent group shows ***P<0.001.

[0039] [Figure 6] Figure 4 shows the results of the statistical analysis of the normalized grayscale values ​​of the IR-B protein band. In the figure, the comparison between the GK rat-dolzagliatin group and the GK rat-solvent group shows ***P<0.001.

[0040] [Figure 7] Western blot bands of glucose transporters 1 and 3 (GLUT1 and GLUT3) and their corresponding internal reference protein GAPDH are shown in the hippocampus of GK rats in the solvent group and GK rats in the doruzagliatin group.

[0041] [Figure 8] Figure 7 shows the results of the statistical analysis of the normalized grayscale values ​​of the GLUT1 band. In the figure, the comparison between the GK rat-dolzagliatin group and the GK rat-solvent group shows **P<0.01**.

[0042] [Figure 9] Figure 7 shows the results of the statistical analysis of the normalized grayscale values ​​of the GLUT2 band. In the figure, the comparison between the GK rat-dolzagliatin group and the GK rat-solvent group shows ***P<0.001.

[0043] [Figure 10] Western blot bands are shown for ion channel glutamate receptor subunits (GluN2A and GluN2B) and their corresponding internal reference protein GAPDH in the hippocampus of GK rats-solvent group and GK rats-dolzagliatin group.

[0044] [Figure 11] Figure 10 shows the results of the statistical analysis of the normalized grayscale values ​​of the GluN2A band. In the figure, the comparison between the GK rat-dolzagliatin group and the GK rat-solvent group shows **P<0.01**.

[0045] [Figure 12] Figure 10 shows the results of statistical analysis of the normalized grayscale values ​​of the GluN2B band. In the figure, the comparison between the GK rat-dolzagliatin group and the GK rat-solvent group shows that ****P<0.0001.

[0046] Specific Embodiments

[0047] In some embodiments, this disclosure relates to the use of glucokinase activators or their prodrugs, or pharmaceutically acceptable salts, isotopes, crystalline forms, hydrates, solvates, diastereomers or enantiomers thereof, in the manufacture of pharmaceuticals for preventing, mitigating, or treating cognitive impairment or neurodegenerative disease in subjects, or for delaying the progression of cognitive impairment or neurodegenerative disease in subjects, or for reducing the risk of developing cognitive impairment or neurodegenerative disease in subjects.

[0048] In some embodiments, the glucokinase activators of the present disclosure include doruzagliatin, AZD1656, pyragliatin, AZD6370, GKA50, YH-GKA, PSN-010, LY2121260, Reishi polysaccharide B, eupatirin, glucollipsin A, glucollipsin B, GKM-001, TTP399, SY-004, TMG-123, AM-9514, AMG-0696, AMG-1694, AMG-3969, LCZ-960, AZD-1092, AZD5658, ARRY-403, and BM. Selected from S-820132, GKM-002, LY2608204, MK-0941, R-1511, RO281675, ZYGK-1, OP-986CR, CM-3, DS-7309, LY-2599506, PF-04937319, PF04991532, TAK-329, PF04991539, TAK-399, or their prodrugs, or at least one of their pharmaceutically acceptable salts, isotope-labeled forms, crystalline forms, hydrates, solvates, diastereomers, or enantiomers.

[0049] In several other embodiments, the disclosure relates to the use of dolzagliatin or its prodrugs, or pharmaceutically acceptable salts, isotopes, crystalline forms, hydrates, solvates, diastereomers or enantiomers thereof, in the manufacture of pharmaceuticals for preventing, mitigating or treating cognitive impairment or neurodegenerative disease in subjects, or for delaying the progression of cognitive impairment or neurodegenerative disease in subjects, or for reducing the risk of developing cognitive impairment or neurodegenerative disease in subjects.

[0050] In some other embodiments, the glucokinase activator of the present disclosure has the following formula: [Table 1] The compound represented by , or its pharmaceutically acceptable salt, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer.

[0051] As an option, the glucokinase activator of this disclosure has the following formula: [Table 2] The compound represented by , or a pharmaceutically acceptable salt thereof, isotope-labeled compound, crystalline form, hydrate, or solvate.

[0052] An option is that the glucokinase activator of this disclosure is dolzagliatin or a pharmaceutically acceptable salt thereof.

[0053] In some other embodiments, the glucokinase activator of the present disclosure is a prodrug of dolzagliatin, or a pharmaceutically acceptable salt thereof, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer.

[0054] An option is that the glucokinase activator of this disclosure is a prodrug of dolzagliatin or a pharmaceutically acceptable salt thereof.

[0055] In some other embodiments, the prodrug of dorzagliatin is a compound disclosed in WO2023 / 040937A1, or a pharmaceutically acceptable salt, isotope-labeled compound, enantiomer, or diastereomer thereof, and the entire disclosure of the above patent application is incorporated herein by reference.

[0056] In some other embodiments, the prodrug of dorzagliatin is of formula (I):

Chemical formula

[0057] Where:

[0058] * indicates a chiral center.

[0059] R1 is selected from H, -C(O)R6, -C(O)OR6, -C(O)NR7R8, -S(O) d ,

[0060] , m , d , m , d ,

[0062] , , m , 1-2 , , , , ,

[0058] , e , d , , m , m , , e , , m , e , , <​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​R3 is independent of H and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Selected from aryls and 5- to 10-membered heteroaryls, R3 may be substituted with 1, 2, 3, 4, or 5 R groups.

[0063] R4 and R5 are independently H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 1-6 Selected from haloalkyl groups. Alternatively, R4, R5, and N atoms combine to form a 3- to 7-membered heterocycline.

[0064] R6 is independently H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 1-6 Selected from haloalkyl groups.

[0065] R7 and R8 are independently H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 1-6 Selected from haloalkyl groups. Alternatively, R7, R8, and the nitrogen atom combine to form a 3- to 7-membered heterocycline.

[0066] R is independent of H, -L-halogen, -L-CN, -L-NO2, and -L-OR. a , -L-SR a -L-NR b R c , -LC(O)OR a -LC(O)NR b R c , -LS(O) m Ure a , -LS(O) m NR b R c , C 1-6Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 The side chains are selected from aryl groups, 5-10 member heteroaryl groups, and native amino acids.

[0067] In the equation, m = 1 or 2.

[0068] R a H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Selected from aryls and 5- to 10-membered heteroaryls.

[0069] R b and R c H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. Or, R b , R c The N atoms then come together to form 3- to 7-membered heterocyclines.

[0070] R d and R e H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 1-6 Selected from haloalkyls, or R d , R e , and the C atoms are grouped together as =O, =S, C 3-7 They form cycloalkyl groups or 3- to 7-membered heterocyclines.

[0071] L is a chemical bond, -C 1-6 Alkylene-,-C 2-6 Alkenylene-, and -C 2-6 Selected from alkynylene-

[0072] In some embodiments, the prodrug of dolzagliatin or a pharmaceutically acceptable salt thereof has the following structure: [ka] It is selected from the following compounds.

[0073] In some other embodiments, the prodrug of doruzagliatin has the following structure: [ka] It is a compound of [the compound].

[0074] In some embodiments, symptoms of cognitive impairment include decreased attention, decreased language ability, decreased spatial and temporal ability, decreased reasoning ability, or decreased judgment.

[0075] For example, cognitive impairments may include the following symptoms: short-term or long-term memory function, learning ability, mental flexibility, attention, executive function, spatial working memory, digital working memory, image recognition, word recognition, test time, mood, energy, anger, hostility, confusion, and general mood disorders.

[0076] In some embodiments, cognitive impairment-related disorders are selected from mild cognitive impairment (MCI), pre-symptomatic Alzheimer's disease, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early-onset Alzheimer's disease, prodromal AD, senile dementia, Lewy body dementia (DLB), microinfarct dementia, AIDS-related dementia, HIV-related dementia, Lewy body-related dementia, Down syndrome-related dementia, frontotemporal dementia, Pick's disease, recent and short-term memory impairment, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, immunodeficiency syndrome-related cognitive impairment, vascular disease-related cognitive impairment, schizophrenia-related cognitive impairment, Parkinson's disease-related cognitive impairment, epilepsy-related cognitive impairment, depression-related cognitive impairment, bipolar disorder-related cognitive impairment, obsessive-compulsive disorder-related cognitive impairment, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning disabilities.

[0077] In some embodiments, cognitive impairment-related disorders are selected from mild cognitive impairment (MCI), pre-symptomatic Alzheimer's disease, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early-onset Alzheimer's disease, prodromal Alzheimer's disease, senile dementia, Lewy body dementia, microinfarct dementia, AIDS-related dementia, HIV-related dementia, Lewy body-related dementia, Down syndrome-related dementia, and vascular disease-related cognitive impairment.

[0078] In one embodiment, the cognitive impairment-related disorder is mild cognitive impairment.

[0079] In one embodiment, the cognitive impairment-related disorder is pre-symptomatic Alzheimer's disease.

[0080] In one embodiment, the cognitive impairment-related disease is Alzheimer's disease.

[0081] In one embodiment, the cognitive impairment-related disease is Alzheimer's disease.

[0082] In one embodiment, the cognitive impairment-related disorder is prodromal Alzheimer's disease.

[0083] In some other embodiments, neurodegenerative diseases include motor neuron diseases (MNDs) such as Parkinson's disease, Alzheimer's disease, prion diseases, and amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), Friedreich's ataxia, Lewy body dementia, epilepsy, encephalitis, hydrocephalus, stroke, chronic traumatic encephalopathy (CTE); synuclein disease; tauopathy; spongiform encephalopathy; familial amyloid polyneuropathy; hereditary cerebral hemorrhage with Dutch amyloidosis; cerebral amyloid angiopathy; Selected from at least one of the following: corticobasal degeneration; Pick's disease; progressive supranuclear palsy; Creutzfeldt-Jakob disease; Gerstmann syndrome; fatal familial insomnia; Kuru disease; bovine spongiform encephalopathy; scrapie; chronic wasting disease; Lewy body Alzheimer's disease; diffuse Lewy body disease; Lewy body dementia; multiple system atrophy; neurodegenerative disease type I with intracerebral iron deposition; diffuse Lewy body disease; frontotemporal lobar degeneration; hereditary dentatorubral-pallidoluysian atrophy; Kennedy disease; Alexander disease; Cockayne syndrome; Icelandic hereditary cerebral amyloid angiopathy.

[0084] In some other embodiments, the neurodegenerative disease is selected from motor neuron diseases (MNDs) such as Parkinson's disease, Alzheimer's disease, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).

[0085] In some other embodiments, the neurodegenerative disease is Alzheimer's disease.

[0086] In some embodiments, the subject has one or more signs selected from type 1 diabetes, type 2 diabetes, early-onset adult-onset diabetes (MODY), gestational diabetes, impaired glucose tolerance, abnormal fasting blood glucose levels, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, cardiovascular disease, insulin resistance, and / or metabolic syndrome.

[0087] In some embodiments, the subject has one or more signs selected from type 1 diabetes, type 2 diabetes, early-onset adult-onset diabetes (MODY), gestational diabetes, impaired glucose tolerance, abnormal fasting blood glucose levels, hyperglycemia, postprandial hyperglycemia, insulin resistance, and / or metabolic syndrome.

[0088] In some embodiments, the subject has one or more signs selected from type 1 diabetes, type 2 diabetes, and insulin resistance.

[0089] In some other embodiments, the subjects have cognitive impairment or neurodegenerative disease and further show signs of insulin resistance or type 2 diabetes.

[0090] In several other embodiments, the Disclosure provides the use of a pharmaceutical composition in the manufacture of a drug for preventing, mitigating, or treating cognitive impairment or neurodegenerative disease in a subject, or for delaying the progression of cognitive impairment or neurodegenerative disease in a subject, wherein the pharmaceutical composition comprises a glucokinase activator or a prodrug thereof, or a pharmaceutically acceptable salt, isotope-labeled form, crystalline form, hydrate, solvate, enantiomer, or diastereomer thereof, and optionally one or more pharmaceutically acceptable excipients.

[0091] In some embodiments, the Disclosure provides a method for preventing, mitigating, or treating cognitive impairment or neurodegenerative disease, or for delaying the progression of cognitive impairment or neurodegenerative disease, or for reducing the risk of developing cognitive impairment or neurodegenerative disease, comprising the step of administering a glucokinase activator or a prodrug thereof, or a pharmaceutically acceptable salt, isotope-labeled compound, crystalline form, hydrate, solvate, diastereomer, or enantiomer thereof, to a subject of interest.

[0092] In one embodiment, the Disclosure provides a method for preventing, reducing, or treating cognitive impairment or neurodegenerative disease, comprising the step of administering a therapeutically effective amount of dorzagliatin or its prodrug, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0093] In one embodiment, the present disclosure provides a method for delaying the progression of cognitive impairment or neurodegenerative disease, comprising the step of administering a therapeutically effective amount of dorzagliatin or its prodrug, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0094] In one embodiment, the disclosure provides a method for reducing the risk of developing cognitive impairment or neurodegenerative disease, comprising the step of administering a therapeutically effective amount of dolzagliatin or its prodrug, or a pharmaceutically acceptable salt thereof, to a subject in need.

[0095] In some embodiments, the glucokinase activators include doruzagliatin, AZD1656, pyragliatin, AZD6370, GKA50, YH-GKA, PSN-010, LY2121260, Reishi polysaccharide B, eupatirin, glucollipsin A, glucollipsin B, GKM-001, TTP399, SY004, TMG-123, AM-9514, AMG-0696, AMG-1694, AMG-3969, LCZ-960, AZD-1092, AZD5658, ARRY-403, and BMS-82. 0132, GKM-002, LY-2608204, MK-0941, R-1511, RO-281675, ZYGK-1, OP-986CR, CM-3, DS-7309, LY-2599506, PF-04937319, PF04991532, TAK-329, PF-04991539, TAK-399, or their prodrugs, or selected from at least one of their pharmaceutically acceptable salts, isotope-labeled forms, crystalline forms, hydrates, solvates, diastereomers, or enantiomers.

[0096] In several other embodiments, the disclosure relates to the use of dolzagliatin or its prodrugs, or pharmaceutically acceptable salts, isotopes, crystalline forms, hydrates, solvates, diastereomers or enantiomers thereof, in the manufacture of pharmaceuticals for preventing, mitigating or treating cognitive impairment or neurodegenerative disease in subjects, or for delaying the progression of cognitive impairment or neurodegenerative disease in subjects, or for reducing the risk of developing cognitive impairment or neurodegenerative disease in subjects.

[0097] In some embodiments, the glucokinase activator is given by the following formula: [Table 3] The compound represented by , or its pharmaceutically acceptable salt, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer.

[0098] In some other embodiments, the glucokinase activator of the present disclosure has the following formula: [Table 4] The compound represented by , or its pharmaceutically acceptable salt, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer.

[0099] In other embodiments, the glucokinase activator is dolzagliatin or a pharmaceutically acceptable salt thereof.

[0100] In some other embodiments, the glucokinase activator is a prodrug of dolzagliatin, or a pharmaceutically acceptable salt thereof, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer.

[0101] In other embodiments, the glucokinase activator is a prodrug of dolzagliatin or a pharmaceutically acceptable salt thereof.

[0102] In some other embodiments, the glucokinase activator is a prodrug of dorzagliatin. The prodrug of dorzagliatin is a compound disclosed in WO2023 / 040937A1, or a pharmaceutically acceptable salt, isotope-labeled compound, enantiomer, or diastereomer thereof, and the entire disclosure of the above patent application is incorporated herein by reference.

[0103] In some other embodiments, the prodrug of dorzagliatin is of formula (I):

Chemical Structure

[0104] Wherein,

[0105] * indicates a chiral center.

[0106] R1 is selected from H, -C(O)R6, -C(O)OR6, -C(O)NR7R8, -S(O) m R6, -S(O) m OR6, and -S(O) m NR7R8.

[0107] R2 is -C(O)R3, -C(O)OR3, -C(O)NR4R5, -S(O) m R3, -S(O) m OR3 and -S(O) m NR4R5.

[0108] Alternatively, R1 and R2 are bonded to form -CHR d -, -SiR d R e -, -C(O)-, -S(O) 1-2 -, -P(O)OR d -, or -CR d R e -CR d R e -.

[0109] R3 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3- to 7-membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, and R3 may be substituted with 1, 2, 3, 4, or 5 R groups.

[0110] R4 and R5 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl. Alternatively, R4, R5, and the N atom together form a 3- to 7-membered heterocyclyl.

[0111] R6 is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl.

[0112] R7 and R8 are independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl. Alternatively, R7, R8, and the nitrogen atom together form a 3- to 7-membered heterocyclyl.

[0113] R is independently selected from H, -L-halogen, -L-CN, -L-NO2, -L-OR a 、-L-SR a 、-L-NR b R c 、-L-C(O)OR a 、-L-C(O)NR b R c 、-L-S(O) m OR<( a 、-L-S(O) m NR It should be noted that there seems to be a small formatting issue in the provided text where "<( a " is likely a typo and should probably be " a ". This has been left as is in the translation to match the original as closely as possible.b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 The side chains are selected from aryl groups, 5-10 member heteroaryl groups, and native amino acids.

[0114] In the equation, m = 1 or 2.

[0115] R a H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Selected from aryls and 5- to 10-membered heteroaryls.

[0116] R b and R c H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. Or, R b , R c The N atoms then come together to form 3- to 7-membered heterocyclines.

[0117] R d and R e H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 1-6 Selected from haloalkyls, or R d , R e , and the C atoms are grouped together as =O, =S, C3-7 They form cycloalkyl groups or 3- to 7-membered heterocyclines.

[0118] L is a chemical bond, -C 1-6 Alkylene-,-C 2-6 Alkenylene-, and -C 2-6 Selected from alkynylene-

[0119] In some embodiments, the prodrug of dolzagliatin or a pharmaceutically acceptable salt thereof has the following structure: [ka] It is selected from the following compounds.

[0120] In some embodiments, the prodrug of doruzagliatin has the following structure: [ka] It is a compound of [the compound].

[0121] In some embodiments, symptoms of cognitive impairment include decreased attention, decreased language ability, decreased spatial and temporal ability, decreased reasoning ability, or decreased judgment.

[0122] For example, cognitive impairments may include the following symptoms: short-term or long-term memory function, learning ability, mental flexibility, attention, executive function, spatial working memory, digital working memory, image recognition, word recognition, test time, mood, energy, anger, hostility, confusion, and general mood disorders.

[0123] In some embodiments, cognitive impairment-related disorders are selected from mild cognitive impairment (MCI), pre-symptomatic Alzheimer's disease, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early-onset Alzheimer's disease, prodromal AD, senile dementia, Lewy body dementia (DLB), microinfarct dementia, AIDS-related dementia, HIV-related dementia, Lewy body-related dementia, Down syndrome-related dementia, frontotemporal dementia, Pick's disease, recent and short-term memory impairment, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, immunodeficiency syndrome-related cognitive impairment, vascular disease-related cognitive impairment, schizophrenia-related cognitive impairment, Parkinson's disease-related cognitive impairment, epilepsy-related cognitive impairment, depression-related cognitive impairment, bipolar disorder-related cognitive impairment, obsessive-compulsive disorder-related cognitive impairment, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning disabilities.

[0124] In some embodiments, cognitive impairment-related disorders are selected from mild cognitive impairment (MCI), pre-symptomatic Alzheimer's disease, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early-onset Alzheimer's disease, prodromal Alzheimer's disease, senile dementia, Lewy body dementia, microinfarct dementia, AIDS-related dementia, HIV-related dementia, Lewy body-related dementia, Down syndrome-related dementia, and vascular disease-related cognitive impairment.

[0125] In one embodiment, the cognitive impairment-related disorder is mild cognitive impairment.

[0126] In one embodiment, the cognitive impairment-related disorder is pre-symptomatic Alzheimer's disease.

[0127] In one embodiment, the cognitive impairment-related disease is Alzheimer's disease.

[0128] In one embodiment, the cognitive impairment-related disease is Alzheimer's disease.

[0129] In one embodiment, the cognitive impairment-related disorder is prodromal Alzheimer's disease.

[0130] In some other embodiments, the range of subjects with cognitive impairment extends from mild cognitive impairment (MCI) to severe cognitive impairment.

[0131] In some other embodiments, the subject with cognitive impairment may have Alzheimer's disease, mild Alzheimer's disease, moderate Alzheimer's disease, or severe Alzheimer's disease.

[0132] In some other embodiments, the subject is human.

[0133] In some other embodiments, neurodegenerative diseases include motor neuron diseases (MNDs) such as Parkinson's disease, Alzheimer's disease, prion diseases, and amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), Friedreich's ataxia, Lewy body dementia, epilepsy, encephalitis, hydrocephalus, stroke, chronic traumatic encephalopathy (CTE); synuclein disease; tauopathy; spongiform encephalopathy; familial amyloid polyneuropathy; hereditary cerebral hemorrhage with Dutch amyloidosis; cerebral amyloid angiopathy; Selected from at least one of the following: corticobasal degeneration; Pick's disease; progressive supranuclear palsy; Creutzfeldt-Jakob disease; Gerstmann syndrome; fatal familial insomnia; Kuru disease; bovine spongiform encephalopathy; scrapie; chronic wasting disease; Lewy body Alzheimer's disease; diffuse Lewy body disease; Lewy body dementia; multiple system atrophy; neurodegenerative disease type I with intracerebral iron deposition; diffuse Lewy body disease; frontotemporal lobar degeneration; hereditary dentatorubral-pallidoluysian atrophy; Kennedy disease; Alexander disease; Cockayne syndrome; Icelandic hereditary cerebral amyloid angiopathy.

[0134] In some other embodiments, the neurodegenerative disease is selected from motor neuron diseases (MNDs) such as Parkinson's disease, Alzheimer's disease, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).

[0135] In some other embodiments, the neurodegenerative disease is Alzheimer's disease.

[0136] In some other embodiments, the subject has one or more signs selected from type 1 diabetes, type 2 diabetes, early-onset adult-onset diabetes (MODY), gestational diabetes, impaired glucose tolerance, abnormal fasting blood glucose levels, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, cardiovascular disease, insulin resistance, and / or metabolic syndrome.

[0137] In some embodiments, the subject has one or more signs selected from type 1 diabetes, type 2 diabetes, early-onset adult-onset diabetes (MODY), gestational diabetes, impaired glucose tolerance, abnormal fasting blood glucose levels, hyperglycemia, postprandial hyperglycemia, insulin resistance, and / or metabolic syndrome.

[0138] In some embodiments, the subject has one or more signs selected from type 1 diabetes, type 2 diabetes, and insulin resistance.

[0139] In some other embodiments, the subjects have cognitive impairment or neurodegenerative disease and further show signs of insulin resistance or type 2 diabetes.

[0140] In some other embodiments, the glucokinase activator may be administered in the form of a pharmaceutical composition. The pharmaceutical composition comprises the glucokinase activator or its prodrug, or an isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer thereof, and optionally one or more pharmaceutically acceptable excipients.

[0141] In some other embodiments, the dose of the glucokinase activator is 0.01 mg to 500 mg, with options of 0.01 mg to 200 mg, and further options of 0.1 mg to 150 mg, such as 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg.

[0142] In some other embodiments, the glucokinase activator is administered orally, parenterally, by inhalation, or topically, with oral administration being an option.

[0143] In some other embodiments, the glucokinase activator is administered for 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years.

[0144] In some other embodiments, the glucokinase activator is administered once, twice, three times, or four times a day, with the option being twice a day.

[0145] In some other embodiments, the glucokinase activator is administered before or after a meal, preferably after a meal.

[0146] In some embodiments, the Disclosure provides glucokinase activators or prodrugs thereof, or pharmaceutically acceptable salts, isotopes, crystalline forms, hydrates, solvates, diastereomers, or enantiomers thereof, used to prevent, mitigate, or treat cognitive impairment or neurodegenerative disease, or to delay the progression of cognitive impairment or neurodegenerative disease, or to reduce the risk of developing cognitive impairment or neurodegenerative disease.

[0147] In some embodiments, the glucokinase activators of the present disclosure include doruzagliatin, AZD1656, pyragliatin, AZD6370, GKA50, YH-GKA, PSN-010, LY2121260, Reishi polysaccharide B, eupatirin, glucollipsin A, glucollipsin B, GKM-001, TTP399, SY004, TMG-123, AM-9514, AMG-0696, AMG-1694, AMG-3969, LCZ-960, AZD-1092, AZD5658, ARRY-403, BMS- 820132, GKM-002, LY-2608204, MK-0941, R-1511, RO-281675, ZYGK-1, OP-986CR, CM-3, DS-7309, LY-2599506, PF-04937319, PF04991532, TAK-329, PF-04991539, TAK-399, or their prodrugs, or selected from at least one of their pharmaceutically acceptable salts, isotope-labeled forms, crystalline forms, hydrates, solvates, diastereomers, or enantiomers.

[0148] In several other embodiments, the disclosure relates to the use of dolzagliatin or its prodrugs, or pharmaceutically acceptable salts, isotopes, crystalline forms, hydrates, solvates, diastereomers or enantiomers thereof, in the manufacture of pharmaceuticals for preventing, mitigating or treating cognitive impairment or neurodegenerative disease in subjects, or for delaying the progression of cognitive impairment or neurodegenerative disease in subjects, or for reducing the risk of developing cognitive impairment or neurodegenerative disease in subjects.

[0149] In some other embodiments, the glucokinase activator of the present disclosure has the following formula: [Table 5] The compound represented by , or its pharmaceutically acceptable salt, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer.

[0150] As an option, the glucokinase activator of this disclosure has the following formula: [Table 6] The compound represented by , or a pharmaceutically acceptable salt thereof, isotope-labeled compound, crystalline form, hydrate, or solvate.

[0151] An option is that the glucokinase activator of this disclosure is dolzagliatin or a pharmaceutically acceptable salt thereof.

[0152] In some other embodiments, the glucokinase activator of the present disclosure is a prodrug of dolzagliatin, or a pharmaceutically acceptable salt thereof, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer.

[0153] An option is that the glucokinase activator of this disclosure is a prodrug of dolzagliatin or a pharmaceutically acceptable salt thereof.

[0154] In several other embodiments, the prodrug of dolzagliatin is a compound disclosed in WO2023 / 040937A1, or a pharmaceutically acceptable salt thereof, isotope-labeled compound, enantiomer, or diastereomer, the entire disclosure of the above patent application is incorporated herein by reference.

[0155] In some other embodiments, the prodrug of doruzagliatin is formula (I): [ka] The compound, or its isotope-labeled derivative, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.

[0156] During the ceremony,

[0157] * indicates a chiral center.

[0158] R1 is H, -C(O)R6, -C(O)OR6, -C(O)NR7R8, -S(O) m R6, -S(O) m OR6 and -S(O) m Selected from NR7R8.

[0159] R2 is -C(O)R3, -C(O)OR3, -C(O)NR4R5, -S(O) m R3, -S(O) m OR3 and -S(O) m Selected from NR4R5.

[0160] Alternatively, R1 and R2 combine to form -CHR d -, -SiR d R e -, -C(O)-, -S(O) 1-2 -, -P(O)OR d -, or -CR d R e -CR d R e -forms

[0161] R3 is independent of H and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Selected from aryls and 5- to 10-membered heteroaryls, R3 may be substituted with 1, 2, 3, 4, or 5 R groups.

[0162] R4 and R5 are independently H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 1-6 Selected from haloalkyl groups. Alternatively, R4, R5, and N atoms combine to form a 3- to 7-membered heterocycline.

[0163] R6 is independently H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6Alkinyl and C 1-6 Selected from haloalkyl groups.

[0164] R7 and R8 are independently H, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 1-6 Selected from haloalkyl groups. Alternatively, R7, R8, and the nitrogen atom combine to form a 3- to 7-membered heterocycline.

[0165] R is independent of H, -L-halogen, -L-CN, -L-NO2, and -L-OR. a , -L-SR a -L-NR b R c , -LC(O)OR a -LC(O)NR b R c , -LS(O) m Ure a , -LS(O) m NR b R c , C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 The side chains are selected from aryl groups, 5-10 member heteroaryl groups, and native amino acids.

[0166] In the equation, m = 1 or 2.

[0167] R a H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Selected from aryls and 5- to 10-membered heteroaryls.

[0168] Rb and R c H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, C 6-10 Selected from aryls and 5-10 member heteroaryls. Or, R b , R c The N atoms then come together to form 3- to 7-membered heterocyclines.

[0169] R d and R e H and C are independent of each other. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl and C 1-6 Selected from haloalkyls, or R d , R e , and the C atoms are grouped together as =O, =S, C 3-7 They form cycloalkyl groups or 3- to 7-membered heterocyclines.

[0170] L is a chemical bond, -C 1-6 Alkylene-,-C 2-6 Alkenylene-, and -C 2-6 Selected from alkynylene-

[0171] In some embodiments, the prodrug of dolzagliatin or a pharmaceutically acceptable salt thereof has the following structure: [ka] It is selected from the following compounds.

[0172] In some other embodiments, the prodrug of doruzagliatin has the following structure: [ka] It is a compound of [the compound].

[0173] In some embodiments, symptoms of cognitive impairment include decreased attention, decreased language ability, decreased spatial and temporal ability, decreased reasoning ability, or decreased judgment.

[0174] For example, cognitive impairments include the following symptoms: short-term or long-term memory function, learning ability, mental flexibility, attention, executive function, spatial working memory, digital working memory, image recognition, word recognition, inspection time, mood, vitality, anger, hostility, confusion, and general mood disorder.

[0175] In some embodiments, the glucokinase activator is for use in preventing, reducing, or treating a cognitive impairment-related disease, or delaying the progression of a cognitive impairment-related disease, or reducing the risk of onset of a cognitive impairment-related disease.

[0176] In some embodiments, the cognitive impairment-related disease is selected from mild cognitive impairment (MCI), pre-onset Alzheimer's disease, Alzheimer's disease, Alzheimer's type dementia, senile dementia, early-onset Alzheimer's disease, prodromal AD, senile dementia, dementia with Lewy bodies (DLB), vascular cognitive impairment, AIDS-related dementia, HIV-related dementia, Lewy body-related dementia, Down syndrome-related dementia, frontotemporal dementia, Pick's disease, recent and short-term memory impairment, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, immunodeficiency syndrome-related cognitive impairment, vascular disease-related cognitive impairment, schizophrenia-related cognitive impairment, Parkinson's disease-related cognitive impairment, epilepsy-related cognitive impairment, depression-related cognitive impairment, bipolar disorder-related cognitive impairment, obsessive-compulsive disorder-related cognitive impairment, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning disorders.

[0177] In some embodiments, the cognitive impairment-related disease is selected from mild cognitive impairment (MCI), pre-onset Alzheimer's disease, Alzheimer's disease, Alzheimer's type dementia, senile dementia, early-onset Alzheimer's disease, prodromal Alzheimer's disease, senile dementia, dementia with Lewy bodies, vascular cognitive impairment, AIDS-related dementia, HIV-related dementia, Lewy body-related dementia, Down syndrome-related dementia, and vascular disease-related cognitive impairment.

[0178] In one embodiment, the cognitive impairment-related disease is mild cognitive impairment.

[0179] In one embodiment, the cognitive impairment-related disease is pre-onset Alzheimer's disease.

[0180] In one embodiment, the cognitive impairment-related disease is Alzheimer's disease.

[0181] In one embodiment, the cognitive impairment-related disease is Alzheimer's type dementia.

[0182] In one embodiment, the cognitive impairment-related disease is prodromal Alzheimer's disease.

[0183] In some other embodiments, neurodegenerative diseases include motor neuron diseases (MNDs) such as Parkinson's disease, Alzheimer's disease, prion diseases, and amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), Friedreich's ataxia, Lewy body dementia, epilepsy, encephalitis, hydrocephalus, stroke, chronic traumatic encephalopathy (CTE); synuclein disease; tauopathy; spongiform encephalopathy; familial amyloid polyneuropathy; hereditary cerebral hemorrhage with Dutch amyloidosis; cerebral amyloid angiopathy; Selected from at least one of the following: corticobasal degeneration; Pick's disease; progressive supranuclear palsy; Creutzfeldt-Jakob disease; Gerstmann syndrome; fatal familial insomnia; Kuru disease; bovine spongiform encephalopathy; scrapie; chronic wasting disease; Lewy body Alzheimer's disease; diffuse Lewy body disease; Lewy body dementia; multiple system atrophy; neurodegenerative disease type I with intracerebral iron deposition; diffuse Lewy body disease; frontotemporal lobar degeneration; hereditary dentatorubral-pallidoluysian atrophy; Kennedy disease; Alexander disease; Cockayne syndrome; Icelandic hereditary cerebral amyloid angiopathy.

[0184] In some other embodiments, the neurodegenerative disease is selected from motor neuron diseases (MNDs) such as Parkinson's disease, Alzheimer's disease, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS).

[0185] In some other embodiments, the neurodegenerative disease is Alzheimer's disease.

[0186] In some embodiments, the subject has one or more signs selected from type 1 diabetes, type 2 diabetes, early-onset adult-onset diabetes (MODY), gestational diabetes, impaired glucose tolerance, abnormal fasting blood glucose levels, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, cardiovascular disease, insulin resistance, and / or metabolic syndrome.

[0187] In some embodiments, the subject has one or more signs selected from type 1 diabetes, type 2 diabetes, early-onset adult-onset diabetes (MODY), gestational diabetes, impaired glucose tolerance, abnormal fasting blood glucose levels, hyperglycemia, postprandial hyperglycemia, insulin resistance, and / or metabolic syndrome.

[0188] In some embodiments, the subject has one or more signs selected from type 1 diabetes, type 2 diabetes, and insulin resistance.

[0189] In some other embodiments, the subjects have cognitive impairment or neurodegenerative disease and further show signs of insulin resistance or type 2 diabetes.

[0190] The glucokinase activators of this disclosure (e.g., dolzagliatin) may contain one or more chiral centers and may therefore exist in various stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds of this disclosure may be in the form of individual enantiomers, diastereomers, or geometric isomers (such as cis and trans isomers), or in the form of a mixture of stereoisomers, such as a racemic mixture or a mixture in which one or more stereoisomers are concentrated. The isomers can be separated from the mixture by methods known to those skilled in the art, such as chiral high-pressure liquid chromatography (HPLC) or the formation and crystallization of chiral salts. Alternatively, optional isomers can be prepared by asymmetric synthesis.

[0191] Those skilled in the art will understand that organic compounds can form complexes with solvents in which they can react or precipitate or crystallize. These complexes are known as “solvates.” When the solvent is water, the complex is known as a “hydrate.” This disclosure encompasses all solvates of the compounds of this disclosure.

[0192] The term "solvate" usually refers to a compound or a salt thereof that has been bonded to a solvent by solvolysis. Such physical bonding may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, and diethyl ether. The compounds described herein can be prepared, for example, in crystalline form and solvated. Preferred solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. For example, solvates can be separated when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvates" encompass both solution-phase solvates and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0193] The term "hydrate" refers to a compound that has bonded with water. Generally, the number of water molecules in a compound hydrate is in a constant ratio to the number of compound molecules in the hydrate. Therefore, a compound hydrate can be represented by a general formula, for example, RxH2O (where R is the compound and x is a number greater than 0). Some compounds can form two or more hydrates, such as monohydrate (x=1), hypohydrate (x is a number greater than 0 and less than 1, such as hemihydrate (R0.5H2O)), and polyhydrate (x is a number greater than 1, such as dihydrate (R2H2O) and hexahydrate (R6H2O)).

[0194] This disclosure also includes compounds labeled with isotopes (isotope variants). These are equivalent to those described in formula (I), but one or more atoms are substituted with atoms that have a different atomic weight or mass number than those commonly found in nature. Examples of isotopes that can be introduced into the compounds of this disclosure include: 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and36 Examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as Cl. Compounds of the Disclosure, their prodrugs, and pharmaceutically acceptable salts of such compounds or prodrugs, all containing the above isotopes and / or other isotopes of other atoms, are included within the scope of the Disclosure. Radioisotopes ( 3 H and 14 Some of the isotope-labeled compounds of this disclosure, such as those incorporating C, can be used to measure the distribution of drugs and / or substrates within tissues. 3 H) and carbon-14 ( 14 C) Isotopes are particularly desirable because they are easy to prepare and detect. Furthermore, deuterium ( 2 Substitution with heavier isotopes such as H) may be an option because it can provide therapeutic benefits through improved metabolic stability, such as extended half-life and reduced dosage in vivo. The isotope-labeled compounds of formula (I) and their prodrugs of this disclosure can generally be prepared by substituting the non-isotope-labeled reagent with an readily available isotope-labeled reagent in the following schemes and / or procedures disclosed in the Examples and Preparation Examples.

[0195] In addition, the context of this disclosure also includes prodrugs. In this specification, the term “prodrug” refers to a compound that exerts its therapeutic effect by releasing an active drug in vivo through enzymatic or non-enzymatic conversion. Examples of pharmaceutically acceptable prodrugs are given in, for example, T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACS Symposium Series, Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra, “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs,” Advanced Drug Delivery Reviews (1996) 19(2) 115-130, which are incorporated herein by reference, respectively.

[0196] Administration

[0197] The glucokinase activators (hereinafter referred to as "compounds") provided in this disclosure are not particularly limited, but can be administered by various routes, including oral administration, parenteral administration, inhalation, topical administration, rectal administration, nasal administration, oral mucosal administration, vaginal administration, and implantation. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-arterial administration, intra-arterial administration, intra-synovial administration, intrasternal administration, intrathecal administration, intrafocal administration, and intracranial injection or infusion techniques.

[0198] Generally, the compounds provided herein are administered in effective doses. The actual amount of compound administered may be determined by a physician, taking into account the condition being treated, the chosen route of administration, the compound actually administered, each patient's age, weight, and response, as well as the severity of the patient's symptoms.

[0199] When used to prevent the conditions disclosed herein, the compounds provided herein are typically administered, under the advice and supervision of a physician, at the dosage levels described above, to subjects at risk of developing such conditions. Subjects at risk of developing a particular condition generally include those with a family history of the condition or those identified by genetic testing or screening as particularly prone to developing the condition.

[0200] The compounds provided herein or pharmaceutical compositions thereof can be administered chronically (“chronic administration”). Chronic administration refers to administering the compound or its pharmaceutical composition over a long period of time, such as for 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, or 10 years, or, for example, continuously and indefinitely over the remaining lifetime of the subject. In some embodiments, chronic administration is intended to maintain a constant blood concentration of the compound over a long period of time, for example within the therapeutic range.

[0201] The pharmaceutical compositions of the present disclosure may be further delivered using various administration methods. For example, in certain embodiments, the pharmaceutical composition may be administered as a bolus, for example to raise the blood concentration of the compound to an effective level. The bolus dose depends on the systemic level of the active ingredient required throughout the body. For example, the active ingredient can be slowly released by intramuscular or subcutaneous bolus administration, while intravenous bolus administration directly (e.g., by infusion) can result in a more rapid delivery and a quick increase in the blood concentration of the active ingredient to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example by infusion, to maintain a steady-state concentration of the active ingredient in the subject. In yet other embodiments, the pharmaceutical composition may first be administered as a bolus and then as a continuous infusion.

[0202] Compositions for oral administration can take the form of bulk liquids or suspensions, or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate precise administration. The term "unit dosage form" refers to a physically separated unit suitable for single-dose administration to human subjects and other mammals, each unit containing a predetermined amount of the active ingredient suitable for producing the desired therapeutic effect, along with appropriate pharmaceutical excipients. Typical unit dosage forms include pre-filled and measured ampoules or syringes for liquid compositions, and pills, tablets, or capsules for solid compositions. In such compositions, the compound is generally present in trace amounts (about 0.1 to about 50% by weight, or optionally about 1 to about 40% by weight), with the remainder being various carriers or excipients and processing aids useful for forming the desired dosage form.

[0203] For oral administration, typical dosing regimens involve 1 to 5 doses per day, particularly 2 to 4 doses, and usually 3 doses per day. Using these dosing patterns, each dose would contain approximately 0.01 to 20 mg / kg of the compound disclosed herein, with optional dosages ranging from approximately 0.1 to 10 mg / kg, particularly 1 to 5 mg / kg.

[0204] The effective dose of the compounds disclosed herein is generally 0.01 mg to 20 mg of the compound per kilogram of patient body weight on average daily, or optionally 0.01 mg to 10 mg of the compound per kilogram of patient body weight, administered as a single or multiple doses. The compounds disclosed herein may generally be administered to patients requiring such treatment in a daily dose range of approximately 0.01 mg to approximately 1000 mg per patient, or optionally 0.01 mg to 500 mg per patient. For example, the daily dose for each patient may be 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, or 500 mg. It may be administered once or more times, for example, once, twice, three times, or four times, on a daily, weekly (or at intervals of several days), or intermittently. For example, the compound may be administered once or more times a day on a weekly basis (e.g., every Monday) and can be continued indefinitely or for several weeks, such as 4 to 10 weeks. Alternatively, the compound may be administered daily for several days (e.g., 2 to 10 days), followed by a break in administration for several days (e.g., 1 to 30 days), and this cycle may be repeated indefinitely or a predetermined number of times, such as 4 to 10 cycles. For example, the compound of this disclosure may be administered daily for 5 days, followed by a 9-day rest period, and then repeated indefinitely or a total of 4 to 10 times.

[0205] The transdermal dose is generally selected to be equal to or less than the blood concentration achieved by the injectable dose. Typically, the dose ranges from approximately 0.01 to approximately 20% by weight, with options ranging from approximately 0.1 to approximately 20% by weight, from approximately 0.1 to approximately 10% by weight, and further options ranging from approximately 0.5 to approximately 15% by weight.

[0206] The injectable dose is in the range of approximately 0.1 mg / kg / hr to at least 10 mg / kg / hr over approximately 1 to 120 hours, and especially over 24 to 96 hours. To ensure a sufficient steady state, a preload bolus of approximately 0.1 mg / kg to 10 mg / kg or more may be administered. For human patients weighing 40-80 kg, the maximum total dose should not exceed approximately 2 g / day.

[0207] Liquid dosage forms suitable for oral administration may contain, in addition to a suitable aqueous or non-aqueous base, buffers, suspending agents, dispersants, colorants, and fragrances. Solid dosage forms may contain, for example, the following components: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; and lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin, or flavorings such as peppermint, methyl salicylate, or orange flavor, or compounds with similar properties.

[0208] Injectable compositions are typically based on sterile saline for injection, phosphate-buffered saline, or other injectable excipients known in the art. As mentioned above, in such compositions, the active compound is usually a trace component of about 0.05 to 10% by weight, with the remainder being injectable excipients, etc.

[0209] Transdermal compositions are typically prepared as topical ointments or creams containing an active ingredient. When prepared as an ointment, the active ingredient is usually mixed with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream using, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art, and generally, the inclusion of additional components makes the active ingredient or formulation more stable and easier to penetrate the skin. All of these known transdermal formulations and components are included within the scope provided herein.

[0210] Furthermore, the compounds described herein can also be administered by transdermal devices. Therefore, drugs can be delivered transdermally using reservoirs, porous membranes, or patches equipped with various solid matrix components.

[0211] The above-mentioned components for orally administered, injectable, or topically administered compositions are merely representative examples. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, and are incorporated herein by reference.

[0212] The compounds of this disclosure can also be administered in sustained-release form or through a sustained-release drug delivery system. A typical description of sustained-release materials is found in Remington's Pharmaceutical Sciences.

[0213] This disclosure also relates to pharmaceutically acceptable formulations of the compounds of this disclosure. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, each consisting of 6, 7, and 8 α-1,4-linked glucose units, and may have one or more substituents on the linked sugar residue, but are not limited to methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substituents. In one embodiment, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, US5,376,645. In one embodiment, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0214] A technical solution or combination thereof in any one of the specific embodiments described above can be combined with a technical solution or combination thereof in any other specific embodiment. While not exhaustively described here for the sake of space, this disclosure is intended to encompass all such combinations of technical solutions. [Examples]

[0215] The materials or reagents used herein are either commercially available or prepared by synthetic methods commonly known in the art.

[0216] The following examples further illustrate embodiments within the scope of this disclosure. However, this disclosure is not limited to these embodiments, and any modifications and substitutions made based on the technical basis of this disclosure are within the scope of protection of this disclosure.

[0217] A prodrug of dolzagliatin was prepared and tested in accordance with the prior art WO2023 / 040937A1.

[0218] Example 1: Dorzagliatin regulated blood glucose homeostasis and delayed the progression of cognitive impairment in GK rats.

[0219] The Goto-Kakizaki (GK) rat is a spontaneously occurring, non-obese type 2 diabetes rat model obtained by repeatedly inbreeding Wistar rats with upper-level glucose tolerance over several generations. GK rats exhibit normal blood glucose levels at birth, but develop overt diabetes with age, showing symptoms such as mild fasting hyperglycemia, marked postprandial hyperglycemia, and insulin resistance. Previous studies have shown that GK rats develop age-related metabolic complications with age, exhibiting a phenotype of memory impairment, as well as measurable cognitive decline and hippocampal synaptic developmental disorders such as decreased expression of synapse-related proteins. The hippocampus is a crucial functional brain region that regulates learning and memory. Due to its progressive diabetic symptoms, typical neurodegenerative disease, and memory impairment, GK rats can be used to evaluate the effectiveness of drugs in preventing memory decline.

[0220] GK rats were randomly assigned to one of the following treatment groups: GK rat-solvent treatment group (n=9) or GK rat-dolzagliatin (8 mg / kg) treatment group (n=8). Age-matched Wistar rats were used as the normal control group, i.e., the Wistar rat-solvent group (n=9). Treatment was initiated at 6 weeks of age. Rats were administered either the solvent or dolzagliatin twice daily via tube in the morning and evening. Peripheral blood was collected from the animals multiple times throughout the growth cycle, and fasting blood glucose levels were tested (fasting blood glucose levels of rats in the three groups were tested and analyzed at weeks 6, 8, 12, 16, 20, 29, and 31).

[0221] The Morris water maze test is a commonly used behavioral test to assess spatial memory, working memory, and spatial discrimination abilities in rodents. By observing and recording the time it takes for animals to find a target object in an opaque pool, the strategies employed, and swimming trajectories, the animal's learning, memory, spatial awareness, and cognitive abilities can be analyzed and estimated.

[0222] The Morris water maze test was conducted approximately 27 weeks after treatment, when the animals were 33 weeks old.

[0223] Preparation of the experimental environment: The laboratory environment was kept quiet. A circular maze / pool (135 cm in diameter, 45 cm in height) was set up. Visual reference points (spatial cues) for the animals to learn were placed on the walls and around the pool. The water temperature in the pool was equalized to room temperature (22°C). The pool area was divided into four virtual quadrants (northeast, northwest, southeast, and southwest), with the northeast quadrant defined as the target quadrant where a hidden escape platform was installed. During the experiment, the time it took for the rats to escape, their swimming path (distance), speed, and quadrant preference were recorded using the ANY-maze system.

[0224] Training Phase: Experimental rats were placed at the starting point of a water maze and allowed to swim freely, searching for a hidden escape platform. Rats that found the platform were allowed to rest on it for 15 seconds. Each training trial lasted 60 seconds. If a rat failed to find the platform within 60 seconds, it was guided to the platform and allowed to remain on it for 15 seconds to experience the sensation of being on the platform. This process resulted in improved learning performance from the second trial onward. Four trials were conducted per day during the training period, with a 30-minute interval between each trial. The location of the hidden platform was not changed during the training period.

[0225] Spatial memory test (probe test): The spatial memory test was conducted 24 hours after the end of the training phase. In the test phase, the hidden platform was removed from the water maze, and rats were placed at the starting point and allowed to swim freely for one minute. The time spent in the original platform quadrant and the swimming distance were recorded, and the data for each animal group was statistically analyzed.

[0226] result

[0227] The data in Figure 1 shows that, with aging, fasting blood glucose levels remained relatively stable in the Wistar rat-solvent group, while blood glucose levels in the GK rat-solvent group gradually increased and were significantly higher than those of the Wistar rat-solvent group (*P<0.05, ***P<0.001, ****P<0.0001; two-way ANOVA, Dunnett's multiple comparison test). Blood glucose levels in the GK rat-dorzagliatin group were significantly lower than those in the GK rat-solvent group (#P<0.05, ##P<0.01; two-way ANOVA, Dunnett's multiple comparison test).

[0228] These data show that fasting blood glucose levels in GK rats-solvent groups gradually increase with age, while long-term administration of low doses of dolzagliatin can delay the rise in fasting blood glucose levels in GK rats.

[0229] The data from Figures 2 and 3 show that in the Morris water maze spatial memory test, both of the following were significantly reduced in the GK rat-solvent group compared to the Wistar rat-solvent group: time spent in the original platform quadrant (Figure 2; mean ± SEM for Wistar rat-solvent group: 22.17 sec ± 1.21 sec; mean ± SEM for GK rat-solvent group: 12.16 sec ± 2.18 sec, **P<0.01, one-way ANOVA, Dunnett's multiple comparison test); swimming distance (Figure 3; mean ± SEM for Wistar rat-solvent group: 4.45 m ± 0.31 m; mean ± SEM for GK rat-solvent group: 2.25 m ± 0.36 m, **P<0.01, one-way ANOVA, Dunnett's multiple comparison test).

[0230] Compared to the Wistar rat-solvent group, the GK rat-dolzagliatin group showed no significant differences in either of the following: time spent in the original platform quadrant (Figure 2; mean ± SEM for Wistar rat-solvent group: 22.17 sec ± 1.21 sec; mean ± SEM for GK rat-dolzagliatin group: 20.1 sec ± 2.56 sec, P=0.7003, one-way ANOVA, Dunnett's multiple comparison test); swimming distance (Figure 3; mean ± SEM for Wistar rat-solvent group: 4.45 m ± 0.31 m; mean ± SEM for GK rat-dolzagliatin group: 4.21 m ± 0.64 m, P=0.9039, one-way ANOVA, Dunnett's multiple comparison test).

[0231] Compared to the GK rat-solvent group, the GK rat-dolzagliatin group showed significant increases in both of the following: time spent in the original platform quadrant (Figure 2; mean ± SEM for the GK rat-solvent group: 12.16 sec ± 2.18 sec; mean ± SEM for the GK rat-dolzagliatin group: 20.1 sec ± 2.56 sec, #P<0.05, one-way ANOVA, Dunnett's multiple comparison test); and swimming distance (Figure 3; mean ± SEM for the GK rat-solvent group: 2.25 m ± 0.36 m; mean ± SEM for the GK rat-dolzagliatin group: 4.21 m ± 0.64 m, ##P<0.01, one-way ANOVA, Dunnett's multiple comparison test).

[0232] These data indicate that GK rats in the solvent group exhibited spatial memory impairment in the Morris water maze spatial memory test at 33 weeks of age, and that long-term treatment with doruzagliatin had a beneficial effect in protecting cognitive function in GK rats.

[0233] Example 2: Dorzagliatin prevented the decrease in insulin receptor (IR) protein expression in the hippocampus of GK rats.

[0234] Animal studies have shown that insulin receptors (IRs) are most abundant in the hippocampus, cerebral cortex, striatum, and cerebellum. The widespread distribution of these receptors in the brain suggests that insulin signaling plays a crucial role, likely involving N-methyl-D-aspartate (NMDA) receptor expression. NMDA receptors are the most important excitatory glutamatergic ion channels in the brain, mediating synaptic transmission and plasticity and regulating various brain functions such as neurodevelopment, learning, and memory. Alterations in insulin signaling in the central nervous system can accelerate brain aging, modulate neuroplasticity, and contribute to neurodegenerative processes. Low levels of insulin receptor expression have been observed in the neuropathology of AD patients. Decreased insulin receptor expression in the rat hippocampus leads to downregulation of NMDA receptor protein expression and spatial learning impairment. Therefore, we evaluated the effect of dolzagliatin on the hippocampal insulin signaling pathway by measuring insulin receptor protein expression levels in the hippocampus of GK rats.

[0235] method

[0236] After 37 weeks of treatment, i.e., at 43 weeks of age, the GK rats were euthanized, and hippocampal tissue was collected and performed Western blotting to detect the expression levels of biomarker proteins.

[0237] (I) Tissue collection

[0238] The animals were rapidly decapitated under anesthesia, and their brains were extracted in a hypothermic environment. The hippocampal tissue was isolated on ice, placed in cryovials, rapidly frozen with liquid nitrogen, and then stored in a -80°C freezer for later use.

[0239] (II) Extraction and quantification of proteins

[0240] (1) The tissue homogenizer (high-throughput tissue homogenizer TissueLyser II, QIAGEN) was pre-cooled to -20°C. The hippocampal tissue was removed from the freezer at -80°C. Protein lysis buffer (RIPA buffer (Solarbio, catalog number R0010) with a protease inhibitor (bimake, catalog number B14001) and a serine protease inhibitor (Solarbio, catalog number P0100) added in a 100:1 ratio) was added, and the tissue was lysed at low temperature to obtain protein homogenates.

[0241] (2) The dissolved protein homogenate was centrifuged at 4°C and 12,000 rpm for 30 minutes using a benchtop high-speed refrigerated centrifuge (Thermo Fisher Scientific, Sorvall ST8R).

[0242] (3) The protein supernatant after centrifugation was collected in a new cryovial, an appropriate amount of protein supernatant was taken, and the concentration was measured using the Pierce® BCA Protein Assay Kit (Thermo Fisher Scientific, catalog number 23227).

[0243] (III) Preparation of denatured protein samples

[0244] Based on the protein concentrations measured in step (II), an appropriate amount of protein lysis buffer was added to adjust the protein concentration of each group to an appropriate level. An equal volume of 2x concentrated protein loading buffer was added, and the resulting mixture was thoroughly mixed by vortexing. The proteins were denatured in a 95°C metal bath for 10 minutes to obtain denatured protein samples. These were cooled to a low temperature and used later.

[0245] (IV) Protein gel electrophoresis

[0246] The denatured protein samples prepared in step (III) were subjected to SDS-polyacrylamide gel electrophoresis. After loading the samples, electrophoresis was started at 70V. When the protein molecular weight standard bands began to disperse, the electrophoresis voltage was adjusted to 110V. Electrophoresis was stopped before the bromophenol blue reached the bottom of the plastic.

[0247] (V) Membrane transfer

[0248] Membrane transfer was performed using the gel obtained after electrophoresis in step (IV). Two isoforms of the insulin receptor (IR) (IR-A protein and IR-B protein) and the internal standard protein GAPDH were transferred to the membrane using a semi-dry transfer method. The membrane was assembled in the order of negative electrode-filter paper-gel-PVDF membrane-filter paper-positive electrode. Membrane transfer was performed at room temperature with a constant current of 0.2 A for 65 minutes.

[0249] After membrane transfer was complete, the PVDF membrane was blocked with non-fat milk at room temperature for 1 hour. The blocked membrane was washed with Tris-buffered saline (TBST) containing 0.1% Tween® 20 surfactant and incubated overnight at 4°C in a slow shaker with the corresponding primary antibody. The primary antibody was removed, and the membrane was washed with TBST to remove any unbound primary antibody. Subsequently, the membrane was incubated at room temperature in a slow shaker for 2 hours with horseradish peroxidase-labeled goat anti-mouse IgG(H+L) (Yisheng, catalog number 33201ES60) / horseradish peroxidase-labeled goat anti-rabbit IgG(H+L) (Yisheng, catalog number 33101ES60P) secondary antibodies. The secondary antibody was removed, and the membrane was washed with TBST to remove any secondary antibody that did not bind to the primary antibody. The eluted PVDF film was scanned using electrochemiluminescence (ECL) with a contact-type nondestructive quantitative imaging device (E-blot) to obtain Western blot images.

[0250] Calculation of relative protein expression levels: Western blot images were quantified using the image processing software ImageJ, and the grayscale values ​​of the target band were measured to characterize the protein expression levels of the target band.

[0251] Target protein normalization: The grayscale values ​​of the target proteins were normalized by dividing them by the grayscale values ​​of the internal reference protein GAPDH. This characterized the relative expression levels of the target bands. The normalized values ​​of each target band were statistically analyzed.

[0252] result

[0253] Figure 4 shows Western blot bands of two insulin receptor isoforms (IR-A protein and IR-B protein) and their corresponding internal reference protein GAPDH in the hippocampus of GK rats in the solvent group and the dolzagliatin group (4 rats in each group). Figures 5 and 6 show the results of statistical analysis of the normalized grayscale values ​​of the IR-A protein band and IR-B protein band from Figure 4, respectively.

[0254] The data in Figures 5 and 6 show that the normalized values ​​of IR-A and IR-B proteins in the hippocampus of the GK rat-dolzagliatin group were significantly larger than those of the GK rat-solvent group (Figure 5; mean ± SEM of GK rat-solvent group: 0.77 ± 0.02; mean ± SEM of GK rat-dolzagliatin group: 1.46 ± 0.08, ***P<0.001, unpaired Student's t-test), (Figure 6; mean ± SEM of GK rat-solvent group: 1.11 ± 0.06; mean ± SEM of GK rat-dolzagliatin group: 1.64 ± 0.06, ***P<0.001, unpaired Student's t-test).

[0255] These data indicate that the relative expression levels of two insulin receptor isoforms in the hippocampus of the GK rat-dolzagliatin group were significantly higher than those of the GK rat-solvent group.

[0256] Example 3: Dorzagliatin stabilized glucose transporter protein expression levels in the hippocampus of GK rats.

[0257] Neurons are energy-consuming cells, the majority of which are used for generating action potentials, synaptic signaling, and neurotransmitter biosynthesis. Glucose is the primary energy source for brain cells, and its membrane transport is regulated by the glucose transporter (GLUT) family. GLUT1 and GLUT3 are the two subtypes with the highest affinity for glucose; neurons primarily take up glucose via GLUT3, while GLUT1 is the primary glucose transporter in astrocytes. GLUT1 can also transport lactate to neurons as an alternative energy source during hypoglycemia. Regulating neuronal metabolism and energy production is essential for cognition and memory, and is dependent on insulin stimulation of GLUTs. Clinical studies have shown that decreased metabolism in certain brain regions of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) patients may be due to reduced expression of GLUT1 and GLUT3 in other brain regions. Reduced GLUT1 and GLUT3 expression and decreased glucose metabolism in the brain have also been observed in rodent models of AD and T2DM. Here, we analyzed the protein expression levels of insulin receptors, major synaptic proteins, and glucose transporters in the hippocampus of GK rats to evaluate the effects of dolzagliatin on hippocampal energy metabolism and insulin signaling pathways.

[0258] method

[0259] Tissue sampling, protein extraction and quantification, preparation of denatured protein samples, and protein gel electrophoresis were sequentially completed using steps (I) to (IV) of Example 2 described above.

[0260] Next, membrane transfer was performed using gels obtained by electrophoresis. GLUT1, GLUT3, and the GAPDH biomarker were transferred to the membrane using a semi-dry transfer method. The membrane was assembled in the following order: negative electrode - filter paper - gel - PVDF membrane - filter paper - positive electrode. Membrane transfer was performed at room temperature with a constant current of 0.2 A for 65 minutes.

[0261] After the membrane transfer was complete, the PVDF membranes (GLUT1, GLUT3, GAPDH) were blocked with non-fat milk for 1 hour at room temperature.

[0262] Calculation of relative protein expression levels: Western blot images were quantified using the image processing software ImageJ, and the grayscale values ​​of target bands were measured to characterize the protein expression levels of the target bands. The grayscale values ​​of the target proteins were normalized by dividing them by the grayscale values ​​of the internal reference protein GAPDH. This characterized the relative expression levels of the target bands. The normalized values ​​of each target band were statistically analyzed.

[0263] result

[0264] Figure 7 shows Western blot bands of glucose transporters 1 and 3 (GLUT1 and GLUT3) and their corresponding internal reference protein GAPDH in the hippocampus of GK rats in the solvent group and the doruzagliatin group (4 rats in each group). Figures 8 and 9 show the results of statistical analysis of the normalized grayscale values ​​of the GLUT1 and GLUT3 bands in Figure 7, respectively.

[0265] The data in Figures 8 and 9 show that the normalized values ​​of the two glucose transporters in the hippocampus of the GK rat-dolzagliatin group were significantly larger than those of the GK rat-solvent group (Figure 8; mean ± SEM of the GK rat-solvent group: 1.38 ± 0.05; mean ± SEM of the GK rat-dolzagliatin group: 1.67 ± 0.06, **P<0.01, unpaired Student's t-test), (Figure 9; mean ± SEM of the GK rat-solvent group: 0.33 ± 0.03; mean ± SEM of the GK rat-dolzagliatin group: 1.22 ± 0.13, ***P<0.001, unpaired Student's t-test).

[0266] The data above indicates that the relative protein expression levels of the two glucose transporters (GLUT1 and GLUT3) in the hippocampus of the GK rat-dolzagliatin group were significantly higher than those of the GK rat-solvent group.

[0267] Example 4: Dorzagliatin inhibited the downregulation of two subunits (GluN2A and GluN2B) of the ion channel glutamate receptor, a major synaptic protein.

[0268] method

[0269] Tissue sampling, protein extraction and quantification, preparation of denatured protein samples, and protein gel electrophoresis were sequentially completed using steps (I) to (IV) of Example 2 described above.

[0270] Next, membrane transfer was performed using gels obtained by electrophoresis. GluN2A and GluN2B biomarkers were transferred to the membrane using a wet transfer method. The membrane was assembled in the following order: negative electrode - sponge - filter paper - gel - PVDF membrane - filter paper - sponge - positive electrode. Membrane transfer was performed in an ice bath at a constant voltage of 100V for 70 minutes.

[0271] After membrane transfer was complete, the PVDF membranes were blocked with BSA or non-fat milk at room temperature for 1 hour (GluN2A and GluN2B membranes were blocked with BSA, and GAPDH membranes were blocked with non-fat milk). The blocked membranes were washed with Tris-buffered saline (TBST) containing 0.1% Tween® 20 surfactant and incubated overnight at 4°C in a slow shaker with the corresponding primary antibody. The primary antibody was removed, and the membrane was washed with TBST to remove any unbound primary antibody. Subsequently, the membranes were incubated at room temperature in a slow shaker for 2 hours with horseradish peroxidase-labeled goat anti-mouse IgG(H+L) (Yisheng, catalog number 33201ES60) / horseradish peroxidase-labeled goat anti-rabbit IgG(H+L) (Yisheng, catalog number 33101ES60P) secondary antibodies. The secondary antibody was removed, and the membrane was washed with TBST to remove any secondary antibody that did not bind to the primary antibody. The eluted PVDF film was scanned using electrochemiluminescence (ECL) with a contact-type nondestructive quantitative imaging device (E-blot) to obtain Western blot images.

[0272] Calculation of relative protein expression levels: Western blot images were quantified using the image processing software ImageJ, and the grayscale values ​​of the target bands were measured to characterize the protein expression levels of the target bands. Normalization of target proteins: The grayscale values ​​of the target proteins were normalized by dividing them by the grayscale values ​​of the internal reference protein GAPDH. This characterized the relative expression levels of the target bands. The normalized values ​​of each target band were statistically analyzed.

[0273] result

[0274] Figure 10 shows Western blot bands of ion channel glutamate receptor subunits (GluN2A and GluN2B) and their corresponding internal reference protein GAPDH in the hippocampus of GK rats in the solvent group and the dolzagliatin group (4 rats in each group). Figures 11 and 12 show the results of statistical analysis of the normalized grayscale values ​​of the GluN2A and GluN2B bands in Figure 10, respectively.

[0275] Figures 11 and 12 show that the normalized values ​​of the two subunits of ion channel glutamate receptors in the hippocampus of the GK rat-dolzagliatin group were significantly larger than those of the GK rat-solvent group (Figure 11; mean ± SEM of GK rat-solvent group: 0.72 ± 0.04; mean ± SEM of GK rat-dolzagliatin group: 1.05 ± 0.07, **P<0.01, unpaired Student's t-test), (Figure 12; mean ± SEM of GK rat-solvent group: 0.55 ± 0.02; mean ± SEM of GK rat-dolzagliatin group: 0.87 ± 0.02, ****P<0.0001, unpaired Student's t-test). This indicates that the relative protein expression levels of two subunits of the ion channel glutamate receptor (GluN2A and GluN2B) in the hippocampus of the GK rat-dorzagliatin group were significantly higher than those of the GK rat-solvent group.

[0276] In summary, in the above examples, long-term treatment with dolzagliatin in GK rats, a rat model of spontaneously occurring type 2 diabetes, can prevent elevated fasting blood glucose and memory impairment in GK rats. GK rats treated with the solvent group showed significantly shorter swimming distance and dwell time in the original platform quadrant in the Morris water maze spatial memory test, indicating impaired spatial memory function compared to Wistar rats treated with the solvent group. Dolzagliatin increased swimming distance and dwell time in the original platform quadrant in the Morris water maze spatial memory test. This indicates that spatial memory function was protected compared to GK rats treated with the solvent group. Long-term treatment with dolzagliatin can prevent a decrease in insulin receptor protein expression in the hippocampus of GK rats and stabilize glucose transporter protein expression levels in the hippocampus of GK rats. Furthermore, long-term treatment with dolzagliatin can inhibit the downregulation of two subunits of the ion channel glutamate receptor, a major synaptic protein. In other words, the above process suggests that it may be a novel mechanism by which dolzagliatin protects memory function.

[0277] Therefore, dolzagliatin, a glucokinase activator, is a promising drug for preventing, alleviating, or treating cognitive impairment or neurodegenerative diseases (such as mild cognitive impairment and Alzheimer's disease) in the target population, or for slowing the progression of cognitive impairment or neurodegenerative diseases in the target population, or for reducing the risk of developing cognitive impairment or neurodegenerative diseases in the target population. The prodrug of dolzagliatin is converted to dolzagliatin in the body (in the gastrointestinal tract and intestinal cells, etc.) before being absorbed into the circulatory system, and this too is a promising drug for preventing, alleviating, or treating cognitive impairment or neurodegenerative diseases (such as mild cognitive impairment and Alzheimer's disease) in the target population, or for slowing the progression of cognitive impairment or neurodegenerative diseases in the target population, or for reducing the risk of developing cognitive impairment or neurodegenerative diseases in the target population.

[0278] The foregoing further describes the disclosure in relation to specific embodiments as options, and the specific embodiments of the disclosure are not limited to this description. Those skilled in the art can make several simple inferences and substitutions without departing from the concepts of the disclosure, which should be considered to be included within the scope of protection of the disclosure.

Claims

1. The use of glucokinase activators or their prodrugs, or their pharmaceutically acceptable salts, isotopes, crystalline forms, hydrates, solvates, diastereomers, or enantiomers, in the manufacture of pharmaceuticals for the prevention, reduction, or treatment of cognitive impairment or neurodegenerative disease in subjects, or for the delay of the progression of cognitive impairment or neurodegenerative disease in subjects, or for the reduction of the risk of developing cognitive impairment or neurodegenerative disease in subjects.

2. The glucokinase activator is given by the following formula: Table 1 The compound represented by, or its pharmaceutically acceptable salt, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer, The option is that the glucokinase activator is dolzagliatin or a pharmaceutically acceptable salt thereof. The use described in claim 1.

3. The glucokinase activator is a prodrug of dolzagliatin, or a pharmaceutically acceptable salt, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer thereof. The options include the glucokinase activator being a prodrug of dolzagliatin or a pharmaceutically acceptable salt thereof. Another option is a prodrug of doruzagliatin, formula (I): 【Chemistry 1】 (In the formula, * indicates a chiral center. R １ is selected from H, -C(O)R ６ , -C(O)OR ６ , -C(O)NR ７ R ８ , -S(O) ｍ R ６ , -S(O) ｍ OR ６ , and -S(O) ｍ NR ７ R ８ ; R ２ Ha-C(O)R ３ , -C(O)OR ３ , -C(O)NR ４ R ５ , -S(O) ｍ R ３ , -S(O) ｍ OR ３ and -S(O) ｍ NR ４ R ５ Selected from; Or, R １ and R ２ The combined form -CHR ｄ -, -SiR ｄ R ｅ -, -C(O)-, -S(O) １－２ -, -P(O)OR ｄ - or -CR ｄ R ｅ -CR ｄ R ｅ - to form; R ３ H and C are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, C ６－１０ Selected from aryls and 5-10 membered heteroaryls, and R ３ It may be substituted with 1, 2, 3, 4, or 5 R groups; R ４ and R ５ H and C are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Selected from haloalkyl groups; or R ４ , R ５ , and the N atoms come together to form 3- to 7-membered heterocyclines; R ６ H and C are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Selected from haloalkyls; R ７ and R ８ H and C are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Selected from haloalkyl groups; or R ７ , R ８ , and nitrogen atoms come together to form 3- to 7-membered heterocyclines; R is independent of H, -L-halogen, -L-CN, and -L-NO ２ , -L-OR ａ , -L-SR ａ , -L-NR ｂ R ｃ , -L-C(O)OR ａ , -LC(O)NR ｂ R ｃ ,-L-S(O) ｍ OR ａ ,-L-S(O) ｍ NR ｂ R ｃ , C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Haloalkyl, C ３－７ Cycloalkyl, 3-7 membered heterocyclyl, C ６－１０ Selected from aryl groups, 5- to 10-membered heteroaryl groups, and side chains of native amino acids; In the formula, m = 1 or 2; R ａ is independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; R ｂ and R ｃ are each independently selected from H, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C １－６ haloalkyl, C ３－７ cycloalkyl, 3- to 7-membered heterocyclyl, C ６－１０ aryl, and 5- to 10-membered heteroaryl; or, R ｂ , R ｃ and the N atom together form a 3- to 7-membered heterocyclyl; R ｄ and R ｅ H and C are independent of each other. １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl and C １－６ Selected from haloalkyls, or R ｄ , R ｅ , and C atoms together =O, =S, C ３－７ Forming cycloalkyl or 3- to 7-membered heterocyclines; L is a chemical bond, -C １－６ Alkylene-, -C ２－６ Alkenylene- and -C ２－６ (Selected from alkynylene) The compound, or its isotope-labeled derivative, enantiomer, diastereomer, or pharmaceutically acceptable salt thereof. The use described in claim 1.

4. The prodrug of dolzagliatin or a pharmaceutically acceptable salt thereof has the following structure: 【Chemistry 2】 Selected from the compounds, The use described in claim 3.

5. The prodrug of doruzagliatin described above has the following structure: 【Transformation 3】 It is a compound of The use described in claim 3.

6. The use according to any one of claims 1 to 5, wherein the symptoms of the cognitive impairment are reduced attention, reduced language ability, reduced spatial and temporal ability, reduced reasoning ability, or reduced judgment.

7. The use described in any one of claims 1 to 6 is for the purpose of preventing, mitigating, or treating cognitive impairment-related disorders, or for the purpose of delaying the progression of cognitive impairment-related disorders, or for the purpose of reducing the risk of developing cognitive impairment-related disorders.

8. The aforementioned cognitive impairment-related disorders are selected from mild cognitive impairment (MCI), pre-symptomatic Alzheimer's disease, Alzheimer's disease (AD), Alzheimer's type dementia, presenile dementia, early-onset Alzheimer's disease, prodromal AD, senile dementia, Lewy body dementia (DLB), microinfarct dementia, AIDS-related dementia, HIV-related dementia, Lewy body dementia, Down syndrome-related dementia, frontotemporal dementia, Pick's disease, recent and short-term memory impairment, age-related cognitive impairment, age-related memory impairment, drug-related cognitive impairment, immunodeficiency syndrome-related cognitive impairment, vascular disease-related cognitive impairment, schizophrenia-related cognitive impairment, Parkinson's disease-related cognitive impairment, epilepsy-related cognitive impairment, depression-related cognitive impairment, bipolar disorder-related cognitive impairment, obsessive-compulsive disorder-related cognitive impairment, post-traumatic stress disorder, attention deficit disorder, attention deficit hyperactivity disorder, and learning disabilities. The options include the aforementioned cognitive impairment-related disorders, selected from mild cognitive impairment (MCI), pre-symptomatic Alzheimer's disease, Alzheimer's disease, Alzheimer's type dementia, presenile dementia, early-onset Alzheimer's disease, prodromal Alzheimer's disease, senile dementia, Lewy body dementia, microinfarct-related dementia, AIDS-related dementia, HIV-related dementia, Lewy body-related dementia, Down syndrome-related dementia, and vascular disease-related cognitive impairment. The options include the cognitive impairment-related disorder being mild cognitive impairment or Alzheimer's disease. The use described in claim 7.

9. The aforementioned neurodegenerative diseases include the following: Parkinson's disease, Alzheimer's disease, prion disease, motor neuron diseases (MND) such as amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), spinocerebellar degeneration (SCA), spinal muscular atrophy (SMA), Friedreich's ataxia, Lewy body dementia, epilepsy, encephalitis, hydrocephalus, stroke, chronic traumatic encephalopathy (CTE); synuclein disease; tauopathy; spongiform encephalopathy; familial amyloid polyneuropathy; hereditary cerebral hemorrhage with Dutch amyloidosis; cerebral amyloid angiopathy; corticobasal degeneration; pip Selected from at least one of the following: Kuru disease; progressive supranuclear palsy; Creutzfeldt-Jakob disease; Gerstmann syndrome; fatal familial insomnia; Kuru disease; bovine spongiform encephalopathy; scrapie; chronic wasting disease; Lewy body Alzheimer's disease; diffuse Lewy body disease; Lewy body dementia; multiple system atrophy; neurodegenerative disease type I with intracerebral iron deposition; diffuse Lewy body disease; frontotemporal lobar degeneration; hereditary dentatorubral-pallidoluysian atrophy; Kennedy disease; Alexander disease; Cockayne syndrome; and Icelandic hereditary cerebral amyloid angiopathy. The options include selecting the aforementioned neurodegenerative disease from Parkinson's disease, Alzheimer's disease, Huntington's disease (HD), and motor neuron diseases (MND) such as amyotrophic lateral sclerosis (ALS). One option is that the aforementioned neurodegenerative disease is Alzheimer's disease. The use according to any one of claims 1 to 8.

10. The aforementioned subjects have one or more symptoms selected from type 1 diabetes, type 2 diabetes, early-onset adult-onset diabetes (MODY), gestational diabetes, impaired glucose tolerance, abnormal fasting blood glucose levels, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, cardiovascular disease, insulin resistance, and / or metabolic syndrome. The options include the subject having one or more symptoms selected from type 1 diabetes, type 2 diabetes, early-onset adult-onset diabetes (MODY), gestational diabetes, impaired glucose tolerance, abnormal fasting blood glucose levels, hyperglycemia, postprandial hyperglycemia, insulin resistance, and / or metabolic syndrome. The options include: the subject has one or more symptoms selected from type 1 diabetes, type 2 diabetes, and insulin resistance. The use according to any one of claims 1 to 9.

11. The use of pharmaceutical compositions in the manufacture of pharmaceuticals for the purpose of preventing, mitigating, or treating cognitive impairment or neurodegenerative disease in a subject, or for the purpose of delaying the progression of cognitive impairment or neurodegenerative disease in a subject, or for the purpose of reducing the risk of developing cognitive impairment or neurodegenerative disease in a subject, The pharmaceutical composition comprises a glucokinase activator or prodrug according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, isotope-labeled form, crystalline form, hydrate, solvate, diastereomer, or enantiomer thereof, and optionally one or more pharmaceutically acceptable excipients. use.

Images