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WO2025184490A1 - N-[4-fluor-5-[[(2s,4r)-4-[(6-méthoxy-4-pyrimidnyl)oxy]-2-méthyl-1-pyrrolidinyl]méthyl]-2-thiazolyl]acétamide destiné à être utilisé dans le traitement de la maladie d'alzheimer - Google Patents

N-[4-fluor-5-[[(2s,4r)-4-[(6-méthoxy-4-pyrimidnyl)oxy]-2-méthyl-1-pyrrolidinyl]méthyl]-2-thiazolyl]acétamide destiné à être utilisé dans le traitement de la maladie d'alzheimer

Info

Publication number
WO2025184490A1
WO2025184490A1 PCT/US2025/017820 US2025017820W WO2025184490A1 WO 2025184490 A1 WO2025184490 A1 WO 2025184490A1 US 2025017820 W US2025017820 W US 2025017820W WO 2025184490 A1 WO2025184490 A1 WO 2025184490A1
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WO
WIPO (PCT)
Prior art keywords
compound
daily dose
pharmaceutically acceptable
acceptable salt
free base
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/017820
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English (en)
Inventor
Flavia Cristina NERY O'DONNELL
Heike HERING
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biogen MA Inc
Original Assignee
Biogen MA Inc
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Filing date
Publication date
Application filed by Biogen MA Inc filed Critical Biogen MA Inc
Publication of WO2025184490A1 publication Critical patent/WO2025184490A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • AD Alzheimer’s disease
  • AD is a progressive brain disorder typically beginning with memory loss and which can lead to severe memory loss, critical thinking, and ability to carry out conversations or respond to one’s environment.
  • AD is the most common type of dementia, however, there is no known cure.
  • approximately 6 million individuals have AD, which is expected to triple to approximately 14 million people by 2060 (Matthews KA et al. Alzheimers Dement. 2019 Jan;15(l): 17-24).
  • AD and a number of related tauopathies including Progressive Supranuclear Palsy (PSP) and some forms of frontotemporal dementia (FTD) are characterized, in part, by the development of neurofibrillary tangles (NFTs).
  • NFTs neurofibrillary tangles
  • PHFs paired helical filaments
  • O-GlcN Ac O-linked P-A-acetylglucosam ine
  • O-GIcN Acasc a major challenge in developing inhibitors for blocking the function of mammalian glycosidases, including O-GIcN Acasc, is the large number of functionally related enzymes present in tissues of higher eukaryotes. Accordingly, the use of non-selective inhibitors in studying the cellular and organismal physiological role of one particular enzyme is complicated because complex phenotypes arise from the concomitant inhibition of such functionally related enzymes. In the case of P-N-acetylglucosaminidases, many existing compounds that act to block O-GIcN Acasc function are non-specific and act potently to inhibit the lysosomal [l-hcxosaminidascs.
  • AD Alzheimer's disease-modifying drugs and standard of care for AD
  • novel therapeutic interventions that attenuate the progression of AD (such as cognitive decline), preserve a patient’s current disease and cognitive state, or improve the disease and cognitive state of the patient.
  • the present disclosure provides methods of treating a human subject with Alzheimer’s disease (AD), the method comprising administering to the subject orally a total daily dose of 0.5 to 50 mg of N-[4-fhioro-5-[[(2S,4R)-4-[(6-methoxy-4- pyrimidinyljoxy] -2-methyl- 1 -pyrrolidinyl]methyl] -2-thiazolyl] acetamide, L-(+)-tartrate salt (1:1) (referred herein as “Compound (I)”: or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 50 mg of Compound (I).
  • AD Alzheimer’s disease
  • the present disclosure provides Compound (I), or a free base or pharmaceutically acceptable salt thereof, for use in the treatment of a human subject with AD, wherein Compound (I) is administered to the subject orally in a total daily dose of 0.5 to 50 mg (e.g., any of total daily doses described herein), or wherein a free base or pharmaceutically acceptable salt of Compound (I) is administered to the subject orally in a an amount equivalent to a total daily dose of 0.5 mg to 50 mg (e.g., any of total daily doses described herein) of Compound (I).
  • a total daily dose of 0.5 to 50 mg e.g., any of total daily doses described herein
  • a free base or pharmaceutically acceptable salt of Compound (I) is administered to the subject orally in a an amount equivalent to a total daily dose of 0.5 mg to 50 mg (e.g., any of total daily doses described herein) of Compound (I).
  • the present disclosure provides the use of Compound (I), or a free base or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a human subject with AD, wherein the medicament comprises Compound (I) in a total daily dose of 0.5 to 50 mg (e.g., any of total daily doses described herein), or a free base or pharmaceutically acceptable salt of Compound (I) in a an amount equivalent to a total daily dose of 0.5 mg to 50 mg (e.g., any of total daily doses described herein) of Compound (I).
  • the present disclosure provides a kit comprising a pharmaceutical composition comprising 0.5 mg to 50 mg (e.g., any of total daily doses described herein) of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 50 mg (e.g., any of total daily doses described herein) of Compound C -
  • FIG. 1 shows the mean plasma concentration of Compound (I) over time in the SAD cohorts.
  • FIG. 2 shows the effect food has on the mean plasma concentration of Compound (I) in the SAD cohorts.
  • FIG. 3 shows the mean plasma concentration of Compound (I) over time in the MAD cohorts.
  • FIG. 4 shows the mean plasma concentration of Compound (I) over time for different age groups in the MAD cohorts.
  • FIG. 5 shows the target occupancy of Compound (I) in the brain over time in the SAD cohorts.
  • FIG. 6 shows the target occupancy of Compound (I) in the brain over time in the MAD cohorts.
  • FIG. 7 shows the target occupancy versus plasma concentration of Compound (I).
  • FIG. 8 shows elevation of O-GlcNAc protein in brain tissue of tau transgenic rTg4510 mice treated with Compound (I).
  • FIG. 9 shows elevation of OGA receptor occupancy in brain tissue of tau transgenic rTg4510 mice treated with Compound (I).
  • FIG. 10 shows inhibition of OGA enzymatic activity in tau transgenic rTg4510 mice treated with Compound (I).
  • FIG. 11 shows reduction of Tau aggregation in tau transgenic rTg4510 mice treated with Compound (I).
  • FIG. 12 shows the increase in O-GlcNAc tau protein that is O-GlcNAcylated at serine 400.
  • the term “free base” refers to a chemical compound substantially free from any salts, i.e. the neutral form of the compound.
  • the free base of Compound (I) is N-(4-Fluoro-5-(((25',47?)-4-((6-methoxypyrimidin-4-yl)oxy)-2- methylpyrrolidin-1- yl)methyl)thiazol-2-yl)acetamide, without the presence of the L-tartrate or other salt.
  • pharmaceutically acceptable salt refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • subject and “patient” are used interchangeably.
  • a subject or a patient is a human patient or human subject.
  • Alzheimer's disease comprises the disease as commonly defined in the art.
  • administer means introducing the compound into the body of the patient in need of treatment.
  • Treating refers to both therapeutic treatment and prophylactic treatment.
  • “Therapeutic treatment” refers to abrogating or improving the cause and/or the effects (i.e., the symptoms, physiological, physical, psychological, emotional or functional manifestations, or any of the clinical parameters or observations) associated with the disorder, disease, condition or syndrome.
  • “Prophylactic treatment” refers to the delay or amelioration or slowing down or prevention of the progression (i.e., the known or expected progression of the disease), severity, and/or duration of the disease or delay or amelioration or slowing down or prevention of the progression of one or more clinical parameters associated with the disease (i.e., “managing” without “curing” the condition), resulting from the administration of one or more therapies.
  • Treating AD according to the invention may involve improving memory, functional capacity, cognition or cognitive function as determined by tools used in the field. It may also involve total or partial reversal of cognitive dysfunction, memory loss, or a loss in functional capacity. It may also involve attenuation or stopping the progression of cognitive impairment, memory loss, or a decline in functional capacity.
  • “Functional capacity” refers to a person’s capability or ability to perform tasks and activities that people find necessary or desirable in their lives in different circumstances or situations. Functional capacity is most appropriately examined with reference to particular life-cycle tasks that an individual may need to perform. For instance, for adults, functional abilities in the labor force are important, as well as activities related to rearing and interacting with their children.
  • Cognitive function refers to one or more higher brain functions that generally involve aspects of thinking and information processing (i.e., cognition). Cognitive function may include attention, focus, reaction time, executive function, conceptual reasoning, memory, processing speed, and psychomotor ability.
  • This monosaccharide is generally referred to as O-linked A-acetylglucosamine or O-GlcN Ac.
  • the enzyme responsible for post-translationally linking P-A-acctylglucosaminc (GlcNAc) to specific serine and threonine residues of numerous nucleocytoplasmic proteins is O-GlcNAc transferase (OGT).
  • a second enzyme known as O-glycoprotein-2-acetamido-2-deoxy-3-D- glucopyranosidase or O-GlcNAcase or OGA, removes this post-translational modification to liberate proteins, making the O-GlcNAc-modification a dynamic cycle occurring several times during the lifetime of a protein.
  • mammalian glycosidases including O-GlcNAcase, comprises a large number of functionally related enzymes present in tissues of higher eukaryotes.
  • the ( -GlcN Acasc inhibitor is a selective O-GlcN Acase inhibitor.
  • the O-GlcNAcase inhibitor is N-(4-Fhioro-5-(((2S,47?)-4-((6- methoxypyrimidin-4-yl)oxy)-2-methylpyrrolidin-l- yl)methyl)thiazol-2-yl)acetamide, L-(+)- tartrate salt (1:1) (also referred herein as “Compound (I)”), or a free base pharmaceutically acceptable salt thereof.
  • Compound (I) is represented by the following structural formula: Compound (I).
  • the present disclosure provides methods of treating a human patient with Alzheimer’s disease (AD) by administering Compound (I) to the subject.
  • AD Alzheimer’s disease
  • the present disclosure provides a method of treating a human subjected with AD, the method comprising administering to the subject orally a total daily dose of 0.5 to 50 mg of N- [4-fhioro-5-[[(2S,4R)-4-[(6-methoxy-4-pyrimidinyl)oxy]-2-methyl-l-pyrrolidinyl]methyl]-2- thiazolyl] acetamide, L-(+)-tartrate salt (1:1) (Compound (I)): or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 50 mg of Compound (I).
  • Compound (I) disclosed herein can be used in the form of a free base or as a salt (preferably, a pharmaceutically acceptable salt).
  • a salt of Compound (I) is 1:1 L-(+)-tartrate salt of N-[4-fhioro-5-[[(2S,4R)-4-[(6-methoxy-4-pyrimidinyl)oxy]-2-methyl-l-pyrrolidinyl]methyl]- 2-thiazolyl] acetamide (free base)
  • a salt of Compound (I) is a salt of the free base compound that is not the 1 : 1 L-(+)-tartrate salt.
  • the salt of Compound (I) is nontartrate salt of the free base.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).
  • Compound (I) is administered as the free base. In some embodiments, in the methods of treatment disclosed herein, a pharmaceutically acceptable salt of Compound (I) is administered.
  • the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%.
  • “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.
  • compositions of the disclosure comprise one or more pharmaceutically acceptable carrier(s) or diluent(s) and Compound (I), or a free base or pharmaceutically acceptable salt thereof.
  • “Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the pharmaceutical compositions of the disclosure without causing a significant adverse toxicological effect on the subject.
  • Nonlimiting examples of pharmaceutically acceptable carriers and/or diluents include NaCl, lactated Ringer’s, normal sucrose, normal glucose, binders, fdlers, disintegrants, lubricants, coatings, sweeteners, flavors, alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, hydroxymethycellulose, fatty acid esters, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such
  • compositions of the disclosure optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose.
  • pharmaceutically acceptable carriers and/or diluents therefor such as lactose, starch, cellulose and dextrose.
  • Other excipients such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes.
  • the subject is administered a total daily dose of 0.5 mg to 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 50 mg of Compound (I).
  • the subject is administered a total daily dose of 0.5 mg to 25 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 25 mg of Compound (I).
  • the subject is administered a total daily dose of 0.5 mg to 20 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 20 mg of Compound (I). In some embodiments, the subject is administered a total daily dose of 0.5 mg to 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 15 mg of Compound (I).
  • the subject is administered a total daily dose of 0.5 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 10 mg of Compound (I).
  • the subject is administered a total daily dose of 0.5 mg to 7.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 7.5 mg of Compound (I).
  • the subject is administered a total daily dose of 0.5 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 5 mg of Compound (I).
  • the subject is administered a total daily dose of 1 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg to 10 mg of Compound (I).
  • the subject is administered a total daily dose of 1 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg to 5 mg of Compound (I).
  • the subject is administered a total daily dose of 0.5 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg to 3 mg of Compound (I).
  • the subject is administered a total daily dose of 1 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg to 3 mg of Compound (I).
  • the subject is administered a total daily dose of 0.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg of Compound (I).
  • the subject is administered a total daily dose of 1 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg of Compound (I).
  • the subject is administered a total daily dose of 1.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1.5 mg of Compound (I). In some embodiment, the subject is administered a total daily dose of 2 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 2 mg of Compound (I).
  • the subject is administered a total daily dose of 2.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 2.5 mg of Compound (I).
  • the subject is administered a total daily dose of 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3 mg of Compound (I).
  • the subject is administered a total daily dose of 3.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3.5 mg of Compound (I).
  • the subject is administered a total daily dose of 4 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 4 mg of Compound (I).
  • the subject is administered a total daily dose of 4.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 4.5 mg of Compound (I).
  • the subject is administered a total daily dose of 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 5 mg of Compound (I).
  • the subject is administered a total daily dose of 5.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 5.5 mg of Compound (I).
  • the subject is administered a total daily dose of 6 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 6 mg of Compound (I).
  • the subject is administered a total daily dose of 6.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 6.5 mg of Compound (I).
  • the subject is administered a total daily dose of 7 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 7 mg of Compound (I). In some embodiment, the subject is administered a total daily dose of 7.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 7.5 mg of Compound (I).
  • the subject is administered a total daily dose of 8 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 8 mg of Compound (I).
  • the subject is administered a total daily dose of 8.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 8.5 mg of Compound (I).
  • the subject is administered a total daily dose of 9 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 9 mg of Compound (I).
  • the subject is administered a total daily dose of 9.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 9.5 mg of Compound (I).
  • the subject is administered a total daily dose of 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 10 mg of Compound (I).
  • the subject is administered a total daily dose of 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 15 mg of Compound (I).
  • the subject is administered a total daily dose of 30 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 30 mg of Compound (I).
  • the subject is administered a total daily dose of 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 50 mg of Compound (I).
  • Compound (I), or a free base or pharmaceutically acceptable salt thereof is administered to the subject once daily. In some embodiments, Compound (I), or a free base or pharmaceutically acceptable salt thereof, is administered to the subject twice daily (BID).
  • the subject is administered a once daily dose of 0.5 mg to 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 50 mg of Compound (I). In some embodiments, the subject is administered a once daily dose of 0.5 mg to 25 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 25 mg of Compound (I).
  • the subject is administered a once daily dose of 0.5 mg to 20 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 20 mg of Compound (I).
  • the subject is administered a once daily dose of 0.5 mg to 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 15 mg of Compound (I).
  • the subject is administered a once daily dose of 0.5 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 10 mg of Compound (I).
  • the subject is administered a once daily dose of 0.5 mg to 7.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 7.5 mg of Compound (I).
  • the subject is administered a once daily dose of 0.5 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 5 mg of Compound (I).
  • the subject is administered a once daily dose of 1 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 1 mg to 10 mg of Compound (I).
  • the subject is administered a once daily dose of 1 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 1 mg to 5 mg of Compound (I).
  • the subject is administered a once daily dose of 0.5 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg to 3 mg of Compound (I).
  • the subject is administered a once daily dose of 1 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 1 mg to 3 mg of Compound (I).
  • the subject is administered a once daily dose of 0.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 0.5 mg of Compound (I). In some embodiment, the subject is administered a once daily dose of 1 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 1 mg of Compound (I).
  • the subject is administered a once daily dose of 1.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 1.5 mg of Compound (I).
  • the subject is administered a once daily dose of 2 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 2 mg of Compound (I).
  • the subject is administered a once daily dose of 2.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 2.5 mg of Compound (I).
  • the subject is administered a once daily dose of 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 3 mg of Compound (I).
  • the subject is administered a total daily dose of 3.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3.5 mg of Compound (I).
  • the subject is administered a once daily dose of 4 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 4 mg of Compound (I).
  • the subject is administered a once daily dose of 4.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 4.5 mg of Compound (I).
  • the subject is administered a once daily dose of 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 5 mg of Compound (I).
  • the subject is administered a once daily dose of 5.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 5.5 mg of Compound (I).
  • the subject is administered a once daily dose of 6 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 6 mg of Compound (I). In some embodiment, the subject is administered a once daily dose of 6.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 6.5 mg of Compound (I).
  • the subject is administered a once daily dose of 7 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 7 mg of Compound (I).
  • the subject is administered a once daily dose of 7.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 7.5 mg of Compound (I).
  • the subject is administered a once daily dose of 8 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 8 mg of Compound (I).
  • the subject is administered a once daily dose of 8.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 8.5 mg of Compound (I).
  • the subject is administered a once daily dose of 9 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 9 mg of Compound (I).
  • the subject is administered a once daily dose of 9.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 9.5 mg of Compound (I).
  • the subject is administered a total daily dose of 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 10 mg of Compound (I).
  • the subject is administered a once daily dose of 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 15 mg of Compound (I).
  • the subject is administered a once daily dose of 30 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 30 mg of Compound (I).
  • the subject is administered a once daily dose of 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a once daily dose of 50 mg of Compound (I). In some embodiments, the subject is administered a dose of 0.25 mg to 25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 25 mg of Compound (I) twice a day.
  • the subject is administered a dose of 0.25 mg to 12.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 12.5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 0.25 mg to 10 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 10 mg of Compound (I) twice a day.
  • the subject is administered a dose of 0.25 mg to 7.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 7.5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 0.25 mg to 5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 5 mg of Compound (I) twice a day'.
  • the subject is administered a dose of 0.25 mg to 3.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 3.75 mg of Compound (I) twice a day.
  • the subject is administered a dose of 0.25 mg to 2.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 2.5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 0.5 mg to 5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.5 mg to 5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 0.5 mg to 2.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.5 mg to 2.5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 0.25 mg to 1.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg to 1.5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 0.5 mg to 1.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.5 mg to 1.5 mg of Compound (I) twice a day. In some embodiment, the subject is administered a dose of 0.25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.25 mg of Compound (I) twice a day.
  • the subject is administered a dose of 0.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 0.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 0.75 mg of Compound (I) twice a day.
  • the subject is administered a dose of 1.0 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 1.0 mg of Compound (I) twice a day.
  • the subject is administered a dose of 1.25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 1.25 mg of Compound (I) twice a day.
  • the subject is administered a dose of 1.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 1.5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 1.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 1.75 mg of Compound (I) twice a day.
  • the subject is administered a dose of 2.0 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 2.0 mg of Compound (I) twice a day.
  • the subject is administered a dose of 2.25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 2.25 mg of Compound (I) twice a day.
  • the subject is administered a dose of 2.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 2.5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 2.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 2.75 mg of Compound (I) twice a day.
  • the subject is administered a dose of 3.0 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 3.0 mg of Compound (I) twice a day.
  • the subject is administered a dose of 3.25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 3.25 mg of Compound (I) twice a day.
  • the subject is administered a dose of 3.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 3.5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 3.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 3.75 mg of Compound (I) twice a day.
  • the subject is administered a dose of 4.0 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 4.0 mg of Compound (I) twice a day.
  • the subject is administered a dose of 4.25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 4.25 mg of Compound (I) twice a day.
  • the subject is administered a dose of 4.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 4.5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 4.75 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 4.75 mg of Compound (I) twice a day.
  • the subject is administered a dose of 5.0 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 5.0 mg of Compound (I) twice a day.
  • the subject is administered a dose of 7.5 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 7.5 mg of Compound (I) twice a day.
  • the subject is administered a dose of 15 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 15 mg of Compound (I) twice a day. In some embodiment, the subject is administered a dose of 25 mg of Compound (I) twice a day, or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a dose of 25 mg of Compound (I) twice a day.
  • Compound (I), or a free base or pharmaceutically acceptable salt thereof is administered to the subject after fasting.
  • Compound (I), or a free base or pharmaceutically acceptable salt thereof is administered to the subject after fasting for at least 8 hours.
  • Compound (I), or a free base or pharmaceutically acceptable salt thereof is administered to the subject after or while eating.
  • kits for treating AD comprising Compound (I), or a pharmaceutically acceptable salt thereof.
  • the kit comprises a pharmaceutical composition comprising 0.5 mg to 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 50 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 0.5 mg to 25 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 25 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 0.5 mg to 20 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 20 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 0.5 mg to 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 15 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 0.5 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 10 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 0.5 mg to 7.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 7.5 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 0.5 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 5 mg of Compound (I). In some embodiments, the kit comprises a pharmaceutical composition comprising 1 mg to 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 1 mg to 10 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 1 mg to 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 1 mg to 5 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 0.5 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 0.5 mg to 3 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 1 mg to 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to 1 mg to 3 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 0.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 0.5 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 1 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 1 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising
  • the kit comprises a pharmaceutical composition comprising 2 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 2 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising
  • the kit comprises a pharmaceutical composition comprising 3 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 3 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising
  • the kit comprises a pharmaceutical composition comprising 4 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 4 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising
  • the kit comprises a pharmaceutical composition comprising 5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 5 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising
  • the kit comprises a pharmaceutical composition comprising 6 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 6 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising
  • the kit comprises a pharmaceutical composition comprising 7 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 7 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising
  • the kit comprises a pharmaceutical composition comprising 8 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 8 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising
  • the kit comprises a pharmaceutical composition comprising 9 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 9 mg of Compound (I). In some embodiments, the kit comprises a pharmaceutical composition comprising 9.5 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 9.5 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 10 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 10 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 15 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 15 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 30 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 30 mg of Compound (I).
  • the kit comprises a pharmaceutical composition comprising 50 mg of Compound (I), or a free base or pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 50 mg of Compound (I).
  • the pharmaceutical composition in the kits comprises a pharmaceutically acceptable carrier in addition to Compound (I) or a free base or pharmaceutically acceptable salt thereof.
  • kits described above further comprise an instruction for using the pharmaceutical composition for treating AD.
  • AD Alzheimer’s disease
  • AUC area under the concentration-time curve
  • AUCinf area under the concentration-time curve from time zero extrapolated to infinity
  • AUCiast area under the concentration-time curve from time zero to time of the last measurable concentration
  • AUCtau area under the concentration-time curve within a dosing interval
  • C-SSRS Columbia Suicide Severity Rating Scale
  • ECG electrocardiogram
  • IV intravenous
  • PET positron emission tomography
  • This FIH study comprised 3 integrated parts: Part A (SAD), Part B (MAD), and Part C (OGA-PET SAD/MAD).
  • This study was designed to evaluate the safety, tolerability, PK, and TO of single- and multiple-ascending doses of oral Compound (I) comprising 3 integrated parts (Part A [SAD], Part B [MAD], and Part C [OGA-PET SAD/MAD]) conducted in healthy adult participants.
  • Females and infertile/vasectomized males were selected as the FIH population. OGA protein levels in the brain are similar between healthy volunteers and patients with AD, indicating that healthy participants are a suitable population for this study.
  • Part of this study included participants aged 65 to 75 years (Part B [MAD]: Cohort 9/Elderly) to reflect the target population and provide a bridge to the Phase 2 development of Compound (I).
  • OGA-PET SAD Approximately 24 participants (healthy females and infertile/vasectomized males) 20 to 64 years of age were to be enrolled in up to 4 OGA-PET SAD cohorts and up to 2 OGA- PET MAD cohorts, with approximately 4 unique participants per cohort.
  • OGA-PET SAD the planned dosing was a single dose of Compound (I) 3 mg orally. Given that a TO of > 90% was achieved at 3 mg, a lower dose of 0.5 mg was implemented.
  • OGA-PET MAD Compound (I) 0.5 mg orally once daily for 14 days was implemented to confirm the predictions of TO > 90% in a multiple-dose setting for Compound (I). The reading confirmed the TO predictions, and no dose escalation above 0.5 mg was implemented for Part C (OGA- PET MAD).
  • a tracer ((S)-N-(5-((3- ((5-fhioropyridin-2-yl)(methyl)amino)piperidin-l- yl)methyl)thiazol-2-yl)[ n C]acetamide) was administered at 200 ⁇ 20 MBq/70 kg of body weight per dose by IV injection prior to each PET scan.
  • Control Matching placebo was administered orally to each cohort following the same dosing regimen as Compound (I).
  • Placebo consisted of size 2 white opaque hypromellose capsules containing 10 mg micro crystalline cellulose excipient.
  • An overview of the treatment groups and integration of study parts is provided in Table 2.
  • the tracer ((S)-N-(5-((3-((5-fhioropyridin-2- yl)(methyl)amino)piperidin-l- yl)methyl)thiazol-2-yl)[ n C]acetamide) was administered by IV injection prior to each PET scan.
  • Table 2 Overview of Treatment Groups and Integration of Study Parts a: Number of unique participants planned per cohort. b: Excluding Part A (SAD: Cohort 3 [fed; Period 2]), doses (morning for Part A
  • Compound (I) was rapidly absorbed, with median T max ranging between 1.0 and 1.5 hours postdose, over the dose range of 0.5 to 50 mg (FIG. 1).
  • the geometric mean ti/2 of Compound (I) was approximately 40 hours for the 0.5 mg dose cohort, and approximately 30 hours in the 1, 3, 15, and 50 mg dose cohorts, demonstrating that once daily dosing is appropriate for Compound (I).
  • Compound (I) systemic exposure increased in an approximately dose-proportional fashion over the dose range of 0.5 to 50 mg.
  • Table 4 Summary of Compound (I) Single Dose PK Data
  • the amount of Compound (I) excreted unchanged in urine was minimal, accounting for approximately 5% or less of the administered dose after multiple oral doses of Compound (I) 15 or 50 mg once daily.
  • Table 5 Summary of Compound (I) Single Dose PK Data
  • the TO of OGA by Compound (I) was assessed in Part C using an OGA-PET tracer, namely (S)-N-(5-((3-((5-fluoropyridin-2-yl)(methyl)amino)piperidin-l- yl)methyl)thiazol-2- yl)[ n C]acetamide (Compound A).
  • OGA-PET tracer namely (S)-N-(5-((3-((5-fluoropyridin-2-yl)(methyl)amino)piperidin-l- yl)methyl)thiazol-2- yl)[ n C]acetamide (Compound A).
  • Each participant received a baseline PET scan (with no administration of Compound (I)) following the IV administration of 200 ⁇ 20 MBq of Compound A in the morning. Acquisition was performed up to 120 minutes and volumes of distribution calculated.
  • Participants then received a predetermined oral dose of Compound (I) at around lunch time; they were administered another IV dose of Compound A and scanned again after an early (between 2 and 6 hours after Compound (I) administration) and late (between 24, 48, or 72 hours after Compound (I) administration) time point. Up to 3 administrations of the PET tracer and 3 PET scans were obtained for each participant. Volumes of distribution were acquired post- treatment with Compound (I). The difference between the baseline and the postdose volumes of distribution (at 2 time points) was used to determine TO in a dose- and time-dependent manner.
  • AEs included headache (33.3% of participants on Compound (I), 11.1% of participants on placebo), dizziness (16.7% of participants on Compound (I), 11.1% of participants on placebo), and tremor (16.7% of participants on Compound (I), 0 participant on placebo).
  • Compound (I) Multiple oral doses of Compound (I) at 0.5 mg were well-tolerated when administered to healthy participants. Three participants (100.0%) experienced at least 1 AE. One participant (33.3%) experienced an AE that was considered related to the study treatment by the Investigator. Medical device site eczema was the most common AE (> 2 participants) reported by participants who received Compound (I) (100.0% of participants).
  • Compound (I) was rapidly absorbed over the dose range of 0.5 to 50 mg.
  • the geometric mean ti/2 of Compound (I) of approximately 30 hours in the 1, 3, 15, and 50 mg dose cohorts demonstrates that once daily dosing is appropriate for Compound (I).
  • Systemic exposure to Compound (I) reaches steady- state after approximately 7 days of once daily administration. There were no time-dependent changes in Compound (I) PK with repeated doses at 15 and 50 mg.
  • Compound (I) exposure (C max , AUCiast, and AUCmf) increased in an approximately dose-proportional fashion over the dose range of 0.5 to 50 mg.
  • Administration of Compound (I) with food did not affect the extent of absorption; however, the rate of oral absorption was reduced.
  • Renal excretion is a minor route of elimination for Compound (I).
  • Example 2 In vivo mouse model study of the effect of OGA inhibition on tau pathology It was further discovered that in mouse models, long-term inhibition of OGA resulted in reduced tau pathology development in brain. rTg4510 mice were treated daily with Compound (I) at 50 mg/kg/day via chow dosing for 16 weeks starting at age 6 weeks, shortly before tau pathology onset, and ending at age 22 weeks, where robust tau pathology can be observed in this model. Brain tissue was analyzed for elevation of O-protein and O-tau (FIGs 8 and 12), ex vivo receptor occupancy (FIG. 9), and OGA enzymatic activity (FIG. 10).
  • NFT-like tau aggregates were reduced by 43% (HTRF assay; FIG. 11); hyperphosphorylated, insoluble tau (64 kDa band) was reduced by 27% (Western blot); and NFT-like tau aggregates were reduced by 20% in the cortex and hippocampus (immunohistochemistry) in Compound (I)-treated animals compared to vehicle-treated animals by the end of the study.

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Abstract

La présente divulgation concerne des méthodes de traitement de la maladie d'Alzheimer (MA) à l'aide du composé (I) tel que représenté par la structure ci-dessous : [Formule doit être insérée ici] ou une base libre ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2025/017820 2024-03-01 2025-02-28 N-[4-fluor-5-[[(2s,4r)-4-[(6-méthoxy-4-pyrimidnyl)oxy]-2-méthyl-1-pyrrolidinyl]méthyl]-2-thiazolyl]acétamide destiné à être utilisé dans le traitement de la maladie d'alzheimer Pending WO2025184490A1 (fr)

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US202463560540P 2024-03-01 2024-03-01
US63/560,540 2024-03-01

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018140299A1 (fr) * 2017-01-27 2018-08-02 Eli Lilly And Company N-[4-fluoro-5-[[(2s,4s)-2-méthyl-4-[(5-méthyl-1,2,4-oxadiazol-3-yl)méthoxy]-1-pipéridyl]méthyl]thiazol-2-yl]acétamide utilisés en tant qu'inhibiteur d'oga
WO2020061150A1 (fr) 2018-09-19 2020-03-26 Biogen Ma Inc. Inhibiteurs d'o-glycoprotéine-2-acétamido-2-désoxy-3-d-glucopyranosidase
WO2022031701A1 (fr) 2020-08-03 2022-02-10 Biogen Ma Inc. Formes cristallines d'un inhibiteur d'o-glycoprotéine-2-acétamido-2-désoxy-3-d-glucopyranosidase

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WO2018140299A1 (fr) * 2017-01-27 2018-08-02 Eli Lilly And Company N-[4-fluoro-5-[[(2s,4s)-2-méthyl-4-[(5-méthyl-1,2,4-oxadiazol-3-yl)méthoxy]-1-pipéridyl]méthyl]thiazol-2-yl]acétamide utilisés en tant qu'inhibiteur d'oga
WO2020061150A1 (fr) 2018-09-19 2020-03-26 Biogen Ma Inc. Inhibiteurs d'o-glycoprotéine-2-acétamido-2-désoxy-3-d-glucopyranosidase
US20220041586A1 (en) * 2018-09-19 2022-02-10 Biogen Ma Inc. O-glycoprotein-2-acetamido-2-deoxy-3-d-glucopyranosidase inhibitors
WO2022031701A1 (fr) 2020-08-03 2022-02-10 Biogen Ma Inc. Formes cristallines d'un inhibiteur d'o-glycoprotéine-2-acétamido-2-désoxy-3-d-glucopyranosidase

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BALANA AT ET AL., BIOCHEM J, vol. 478, no. 14, 30 July 2021 (2021-07-30), pages 2733 - 2758
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MATTHEWS KA ET AL., ALZHEIMERS DEMENT, vol. 15, no. 1, January 2019 (2019-01-01), pages 17 - 24
ZHANG TINGTING ET AL: "Different Doses of Pharmacological Treatments for Mild to Moderate Alzheimer's Disease: A Bayesian Network Meta-Analysis", FRONTIERS IN PHARMACOLOGY, vol. 11, 26 May 2020 (2020-05-26), CH, XP093276289, ISSN: 1663-9812, DOI: 10.3389/fphar.2020.00778 *

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