US-20260124200-A1 - METHOD OF TREATING NEURODEGENERATIVE DISEASES

Abstract

Disclosed is a method of treating a disease or condition characterized by neurodegeneration via administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of hinokitiol, hinokitiol derivatives, and iron-transporting tropolones.

Inventors

• Martin D. Burke
• Stella EKAPUTRI
• Samantha Taylor BROWN
• Nathan Eric SCHROEDER
• Young Ah SEO

Assignees

• THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS
• THE REGENTS OF THE UNIVERSITY OF MICHIGAN

Dates

Publication Date

20260507

Application Date

20231002

Claims (20)

1. 1 . A method of treating a disease or condition selected from the group consisting of an inflammatory disorder leading to an abnormal suppression of ferroportin production, a neurodegeneration with brain iron accumulation (NBIA), a Beta-propeller Protein-associated Neurodegeneration (BPAN), a Pantothenate Kinase-associated Neurodegeneration (PKAN), a PLA2G6-associated Neurodegeneration (PLAN), a Mitochondrial-membrane Protein-associated Neurodegeneration (MPAN), a Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN), a COASY Protein-Associated Neurodegeneration (CoPAN), a Aceruloplasminemia, a Kufer-Rakeb Syndrome, a Parkinson's Disease 9 (PARK9), a Neuroferritinopathy, a Woodhouse-Sakati Syndrome, and an Idiopathic NBIA, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of hinokitiol, hinokitiol derivatives, and iron-transporting tropolones.
2. 2 . A method of treating a disease or condition selected from the group consisting of an inflammatory disorder leading to an abnormal suppression of ferroportin production, a neurodegeneration with brain iron accumulation (NBIA), a Beta-propeller Protein-associated Neurodegeneration (BPAN), a Pantothenate Kinase-associated Neurodegeneration (PKAN), a PLA2G6-associated Neurodegeneration (PLAN), a Mitochondrial-membrane Protein-associated Neurodegeneration (MPAN), a Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN), a COASY Protein-Associated Neurodegeneration (CoPAN), a Aceruloplasminemia, a Kufer-Rakeb Syndrome, a Parkinson's Disease 9 (PARK9), a Neuroferritinopathy, a Woodhouse-Sakati Syndrome, and an Idiopathic NBIA, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, having a structure according to Formula (Ia): wherein: X represents oxygen or sulfur; R a represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl; R a ′ represents hydrogen, halo, alkyl, or substituted alkyl; and R b , R c , and R d are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyloxy, substituted cycloalkyloxy, heterocycloalkyloxy, substituted heterocycloalkyloxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, and heteroalkynyl; provided that R a , R b , R c , and R d are not all hydrogen.
3. 3 . The method of claim 2 , wherein R a ′ is hydrogen.
4. 4 . The method of claim 2 , wherein R a ′ is halo.
5. 5 . The method of claim 2 , wherein R a ′ is alkyl, or substituted alkyl.
6. 6 . The method of any one of claims 2-5 , wherein at least one of R a , R b , R c , and R d is selected from the group consisting of halo, alkyl, substituted alkyl, heteroalkyl, alkylcycloalkyl, alkylheterocycloalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyloxy, substituted cycloalkyloxy, heterocycloalkyloxy, substituted heterocycloalkyloxy, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl.
7. 7 . The method of any one of claims 2-6 , wherein at least one of R a , R a ′, R b , R c , and R d is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl.
8. 8 . The method of claim 2 or 3 , wherein the compound is represented by Formula Ib: wherein: R a represents hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, or heteroalkynyl; and R b , R c , and R d are independently selected from the group consisting of hydrogen, halo, alkyl, substituted alkyl, heteroalkyl, alkoxy, substituted alkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, alkenyl, substituted alkenyl, heteroalkenyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkenyl, substituted heterocycloalkenyl, alkynyl, substituted alkynyl, and heteroalkynyl; provided that R a , R b , R c , and R d are not all hydrogen.
9. 9 . The method of any one of claims 2-8 , wherein: each occurrence of heterocycloalkyl is independently selected from the group consisting of: n is independently for each occurrence an integer selected from 0-5 inclusive; R 2b is independently for each occurrence hydrogen, alkyl, substituted alkyl, heteroalkyl, hydroxy, alkoxy, substitutedalkoxy, alkoxyalkyl, substituted alkoxyalkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, and substituted alkynyl; and each instance of R 2 independently represents —F, alkyl, haloalkyl, or alkoxy; or two geminal instances of R 2 represent carbonyl.
10. 10 . The method of any one of claims 2-9 , wherein R a represents —F, —CF 3 , (C2-C15)alkyl, or substituted (C1-C15)alkyl.
11. 11 . The method of claim 10 , wherein: R b , R c , and R d independently represent hydrogen, (C1-C15)alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, (C1-C15)alkylene-R 1 , 3-12 membered cycloalkyl-R 1 , or 3-12 membered heterocycloalkyl-R 1 ; and R 1 represents independently for each occurrence halo, alkyl, alkoxy, or hydroxyl.
12. 12 . The method of claim 8 , wherein at least one of R a , R b , R c , and R d is selected from the group consisting of methyl, ethyl, n-propyl, and isopropyl.
13. 13 . The method of any one of claims 11-12 , wherein said compound is selected from the group consisting of:
14. 14 . The method of claim 13 , wherein said compound is
15. 15 . The method of claim 13 , wherein said compound is
16. 16 . The method of claim 11 , wherein said compound is selected from the group consisting
17. 17 . The method of claim 11 , wherein said compound is
18. 18 . The method of any one of claims 2-9 , wherein R a represents —Cl, —F, —CF 3 , (C2-C15)alkyl, or substituted (C1-C15)alkyl.
19. 19 . The method of any one of claim 18 , wherein R a represents —F.
20. 20 . The method of any one of claims 18-19 , wherein: R b , R c , and R d independently represent hydrogen, halo (C1-C15)alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, (C1-C15)alkylene-R 1 , 3-12 membered cycloalkyl-R 1 , or 3-12 membered heterocycloalkyl-R 1 ; and R 1 represents independently for each occurrence halo, alkyl, alkoxy, or hydroxyl.

Description

RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63/411,902, filed Sep. 30, 2022. STATEMENT OF GOVERNMENT SUPPORT This invention was made with government support under 1R01HL140526 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Iron misdistribution underlies many neurodegenerative diseases. For example, the most prevalent neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are associated with brain iron accumulation that progressively increases with age. Less prevalent diseases, such as Friedreich's ataxia and Huntington's disease, are also characterized by abnormal iron accumulation in the brain. Specifically, it has been reported that Friedreich's ataxia patients accumulate iron inside the mitochondria, which suggests that cellular iron misdistribution also contributes to the pathology. See Michael Li-Hsuan Huang, Darius J. R. Lane, and Des R. Richardson; “Mitochondrial Mayhem: The Mitochondrion as a Modulator of Iron Metabolism and Its Role in Disease”; Antioxidants & Redox Signaling, 2011, 15:12, 3003-3019. Significant correlation between brain iron overload and neurodegeneration is also observed in the disease known as neurodegeneration with brain iron accumulation (NBIA), a group of inherited neurological disorders marked by neurological deterioration in early adulthood along with progressive dystonia, Parkinsonism, cognitive decline, and seizures. The innate ability of iron to act as both an electron acceptor and an electron donor makes it essential for most living organisms. The iron demand is particularly high in the brain, the most metabolically active organ in the body, as iron is needed for oxidative metabolism, mitochondrial energy generation, synaptic plasticity, myelination, and the synthesis of neurotransmitters. However, excess iron, especially in Fe(II) form, is neurotoxic because of its ability to generate deleterious reactive oxygen species (ROS) via the Fenton reaction of the Haber-Weiss cycle, resulting in oxidative injury that can lead to cell death. Therefore, brain iron overload is a critical yet underappreciated factor that contributes to neurodegenerative diseases. The effective reversal of brain iron overload will require compounds that enable site-specific transmembrane iron mobilization in a safe manner by maintaining bound iron as Fe(III). Ideally, these molecules would also functionally interface with endogenous iron-binding small molecules and proteins. Currently, iron chelators, such as deferasirox (DFX) and deferiprone (DFP), are promising drug candidates for protection against iron-associated neurodegeneration. However, DFP can cause serious side effects, such as agranulocytosis, arthropathy, gastrointestinal bleeding, ophthalmic/auditory toxicity, the loss of essential nutrients (zinc and copper), and neurological complications. Moreover, DFP and other clinically approved iron chelators operate primarily by removing iron that has already been released from cells; i.e., they cannot directly transport iron across lipid bilayers. Thus, their potential for removing iron from neurons and/or their supporting cells is limited. Accordingly, there exists a need for a new method of treatment for neurodegenerative diseases that is highly specific, well-tolerated, and can serve as a useful therapy. SUMMARY In certain embodiments, the present disclosure is to a method of treating a disease or condition selected from the group consisting of an inflammatory disorder leading to an abnormal suppression of ferroportin production, a neurodegeneration with brain iron accumulation (NBIA), a Beta-propeller Protein-associated Neurodegeneration (BPAN), a Pantothenate Kinase-associated Neurodegeneration (PKAN), a PLA2G6-associated Neurodegeneration (PLAN), a Mitochondrial-membrane Protein-associated Neurodegeneration (MPAN), a Fatty Acid Hydroxylase-Associated Neurodegeneration (FAHN), a COASY Protein-Associated Neurodegeneration (CoPAN), a Aceruloplasminemia, a Kufer-Rakeb Syndrome, a Parkinson's Disease 9 (PARK9), a Neuroferritinopathy, a Woodhouse-Sakati Syndrome, and an Idiopathic NBIA, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of hinokitiol, hinokitiol derivatives, and iron-transporting tropolones. In certain embodiments, the present disclosure provides a method of treating a disease or condition a disease or condition selected from the group consisting of an inflammatory disorder leading to an abnormal suppression of ferroportin production, a neurodegeneration with brain iron accumulation (NBIA), a Beta-propeller Protein-associated Neurodegeneration (BPAN), a Pantothenate Kinase-associated Neurodegeneration (PKAN), a PLA2G6-associated Neurodegeneration (PLAN), a Mitochondrial-membrane Protein-associated Neurodegeneration (MPAN), a Fatty Acid Hydroxyla