Combining BACE1 inhibitors with mGluR agonists for Alzheimer's disease therapy
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Publication Number
US-12156879-B2
Publication Date
2024-12-03
Expiration Date
Abstract
Disclosed pharmaceutical compositions including a Beta site APP Cleaving Enzyme (BACE1) inhibitor and an metabotropic glutamate receptor (mGluR) agonist, and methods for use of such compositions to treat Alzheimer's disease (AD), Down's syndrome, Parkinson's disease, vascular dementia, Dementia with Lewy Bodies, dementia, and/or frontal temporal dementia.
Core Innovation
The disclosure describes a pharmaceutical approach for improving cognitive function in a subject having a disorder selected from Alzheimer's disease (AD), Down's syndrome, Parkinson's disease, vascular dementia, Dementia with Lewy Bodies, and/or frontal temporal dementia. The approach comprises administering an amount effective to treat the disorder, including a Beta site APP Cleaving Enzyme 1 (BACE1) inhibitor and a metabotropic glutamate receptor (mGluR) agonist.
The rationale stated in the disclosure is that BACE1 inhibition reduces amyloid deposition, while also potentially worsening cognition through synaptic deficits. The disclosure describes that enhancing group I mGluR activity, including mGluR1/5, counteracts the cognitive decline associated with synaptic deficits that can occur with BACE1 inhibition.
The disclosure further states experimental evidence that BACE1 deficiency or inhibition reduces synaptic proteins including mGluR1 and PSD-95 and reduces long-term potentiation (LTP). The disclosure reports that mGluR1-positive allosteric modulators, including Ro0711401, CHPG, and Ro67-7476, reverse or mitigate LTP and improve learning and memory in mouse behavioral assays.
The disclosure describes example BACE1 inhibitors and example mGluR agonists, and it also discusses administration options including co-administration versus sequential administration. The disclosure additionally describes subject stratification, including APOE ε4 and AD-related gene mutations, in connection with the treated population.
Claims Coverage
The independent claim provides claim coverage for a method of improving cognitive function by administering a selected BACE1 inhibitor and a selected mGluR agonist to a subject with a specified disorder. The independent claim includes two major inventive elements: the paired selection of a BACE1 inhibitor and an mGluR agonist, and the improvement of cognitive function for subjects with listed neurocognitive disorders.
Improving cognitive function with a BACE1 inhibitor and an mGluR agonist
Administering to a subject an amount effective to improve cognitive function in a disorder selected from Alzheimer's disease, Down's syndrome, Parkinson's disease, vascular dementia, Dementia with Lewy Bodies, and/or frontal temporal dementia, comprising administering a BACE1 inhibitor and an mGluR agonist, each selected from defined groups (or pharmaceutically acceptable salts).
Selected BACE1 inhibitor for the cognitive function method
The BACE1 inhibitor is selected from SCH1682496, 6-(3-chloro-5-(5-prop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-2-imino-3,6-dimethyltetrahydropyrimidin-4(1H)-one, LY2811376, verubecestat, lanabecestat, umibecestat, elenbecestat, atabecestat, LY3202626, and AZD3839, or a pharmaceutically acceptable salt thereof.
Selected mGluR agonist for the cognitive function method
The mGluR agonist is selected from CHPG, VU 0422288, DHPG, (R,S)-3,5-dihydroxyphenylglycine, quisqualate, trans-azetidine-2,3-dicarboxylic acid, 3-hydroxyphenylglycine, VU6000799, VU6000790, ACPT1, (R,S)-PPG, Ro 67-7476, and Ro0711401, or a pharmaceutically acceptable salt thereof.
Overall claim coverage centers on administering a defined pair of agents—a selected BACE1 inhibitor and a selected mGluR agonist—to improve cognitive function in subjects with specified neurocognitive disorders, with further dependent claim refinements based on particular disorders, selected agents, administration patterns, and stratification features such as APOE ε4 and AD-related gene mutations.
Stated Advantages
Improving cognitive function in a subject with a disorder selected from Alzheimer's disease (AD), Down's syndrome, Parkinson's disease, vascular dementia, Dementia with Lewy Bodies, and/or frontal temporal dementia.
Documented Applications
A method for improving cognitive function in subjects with Alzheimer's disease (AD).
A method for improving cognitive function in subjects with Down's syndrome, Parkinson's disease, vascular dementia, Dementia with Lewy Bodies, and/or frontal temporal dementia.
Treatment of a subject by administering an amount effective to treat the disorder using a BACE1 inhibitor and an mGluR agonist, including subject stratification using APOE ε4 and/or AD-related gene mutations in the treated population.
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