Casein kinase 1 delta inhibitor
Inventors
PIKE, IAN H. • Kuhn, Karsten • Kienle, Stefan • Hamilton, William D. O. • Heal, Jonathan R. • Sheridan, Joseph M.
Assignees
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Publication Number
US-10815230-B2
Publication Date
2020-10-27
Expiration Date
Abstract
The present invention provides 2-Methyl-amino-3-[(4-fluorophenyl)carbonyl]indolizine-1-carboxamide of formula (I) or a pharmaceutically acceptable salt thereof; and its therapeutic uses in the treatment of neurodegenerative disorders, in particular tauopathies and most preferably in the treatment of Alzheimer's disease.
Core Innovation
The invention relates to a casein kinase 1 delta inhibitor, 2-Methyl-amino-3-[(4-fluorophenyl)carbonyl]indolizine-1-carboxamide (Compound A), and pharmaceutically acceptable salts thereof. It is provided as a pharmaceutical composition for therapeutic use. The approach is framed around inhibiting casein kinase 1 delta (CSNK1D) activity in neurodegenerative disorders, including tauopathies and Alzheimer’s disease.
The problem addressed is the involvement of CSNK1D in Alzheimer’s disease and tau phosphorylation, and the need for selectivity and brain permeability over prior CSNK1D inhibitors. The document states that improved potency and selectivity are achieved through mono-methylation of a prior indolizine carboxamide scaffold. The rationale ties CSNK1D inhibition to effects associated with tau phosphorylation in the treatment context.
The disclosure supports the invention with biological profiling and in vivo assessment, including kinase binding/selectivity profiling (KINOMEscan), potency values (IC50), and cytotoxicity screening, together with pharmacokinetics in CD-1 mice. It further includes in vivo cognitive efficacy in TMHT (Thy-1 Mutated Human Tau) transgenic mice using the Morris water maze, and detection of compound presence in plasma and brain. The document also describes physicochemical and BBB-related parameters in support of brain exposure.
Claims Coverage
The claims include one independent claim directed to the disclosed compound structure (or a pharmaceutically acceptable salt), with additional dependent claims focusing on pharmaceutical compositions and therapeutic methods, particularly inhibiting casein kinase 1 delta activity and treating Alzheimer’s disease. The independent claim contains one core inventive subject matter: the compound structure or its pharmaceutically acceptable salt.
Disclosed compound structure and pharmaceutically acceptable salt
A compound having the structure (or a pharmaceutically acceptable salt thereof).
Independent claim coverage centers on the disclosed compound structure (or its pharmaceutically acceptable salt), with the overall claim set further directed in dependent claims toward pharmaceutical compositions and therapeutic use for inhibiting casein kinase 1 delta activity and treating Alzheimer’s disease.
Stated Advantages
Improved potency and selectivity compared with prior CSNK1δ inhibitors, as attributed to mono-methylation of a prior indolizine carboxamide scaffold.
Brain exposure support based on detection of compound presence in plasma and brain and favorable BBB-related physicochemical parameters.
In vivo cognitive efficacy in TMHT transgenic mice as assessed in the Morris water maze.
Documented Applications
Therapeutic use for neurodegenerative disorders, especially tauopathies and Alzheimer’s disease (AD), via inhibition of casein kinase 1 delta activity.
Treatment of Alzheimer’s disease in a subject by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt.
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