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Systemic Administration of a Brain Permeable Cdk5 Inhibitor Alters Neurobehavior.
Alan Umfress1, Sarbjit Singh2, Kevin J Ryan3
1Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, United States.
Frontiers in Pharmacology
|June 1, 2022
Summary
A novel brain-penetrant drug, 25-106, inhibits Cyclin-dependent kinase 5 (Cdk5). This discovery offers potential new treatments for neurological and neuropsychiatric disorders by targeting Cdk5 activity.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Discovery
Background:
- Cyclin-dependent kinase 5 (Cdk5) regulates neuronal signaling and is implicated in neuropsychiatric and neurodegenerative diseases.
- Current treatments for these conditions are limited, and effective, systemically deliverable Cdk5 inhibitors are lacking.
Purpose of the Study:
- To identify and characterize novel, brain-penetrant inhibitors of Cdk5 for potential therapeutic use.
- To evaluate the efficacy of a novel Cdk5 inhibitor in preclinical models.
Main Methods:
- Screening of aminopyrazole analogs to identify Cdk5 inhibitors.
- Pharmacokinetic and pharmacodynamic characterization of the lead compound 25-106 in mice.
- Functional validation of Cdk5 inhibition using behavioral tests (open field, tail-suspension).
Main Results:
- Identification of 25-106, a novel aminopyrazole analog with potent brain penetration and Cdk5 inhibitory activity.
- Demonstration of favorable pharmacokinetic and dynamic profiles for 25-106 in mice.
- Validation of Cdk5 inhibition's therapeutic potential through observed behavioral changes.
Conclusions:
- 25-106 is a promising preclinical Cdk5 inhibitor suitable for systemic administration.
- This novel compound holds significant potential for treating a range of neurological and neuropsychiatric conditions.
