Tricyclic Dibenzothiazepine Compounds Modulate CDKL5 Kinase Activity
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Solution Overview
Problem
Current treatments lack effective solutions for CDKL5 disorder, a neurodevelopmental disorder characterized by early-onset epileptic encephalopathy, motor rigidity, and impaired learning, with no clear relationship between mutation type or location and symptom severity, and existing compounds have not been evaluated for their effects on CDKL5 disorder.
Innovation Solution
Tricyclic dibenzothiazepine compounds, such as tianeptine and its metabolites, are administered to treat CDKL5 disorder by modulating CDKL5 kinase activity, affecting AMPA receptor subunit GluR2 expression and phosphorylation, thereby addressing motor deficits and other symptoms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing compounds are used for treatment, then general neurodegenerative pathologies may be addressed, but CDKL5 disorder specifically remains untreated
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of dibenzothiazepine compounds (Formula I) to create derivatives with optimized pharmacological properties for CDKL5 disorder treatment, while maintaining the core structural framework that provides general neuroprotective effects
2Reliability
If CDKL5 kinase activity is modulated to improve neuronal function, then motor deficits are addressed, but potential off-target effects on other kinase substrates may occur
Solution Approach 1:
The patent applies local quality by designing compounds that target specific kinase activity patterns in neuronal tissues affected by CDKL5 disorder, particularly focusing on GluR2 phosphorylation at Ser880, while minimizing effects on other kinase substrates through selective molecular interactions
Data Source
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AI summary
Tricyclic dibenzothiazepine compounds for use in the treatment of CDKL5 disorder. Specifically, a compound of Formula I, or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity for use in the treatment of CDKL5 disorder in a mammal, wherein a compound of Formula I comprises: (i) formula 1 or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, wherein: R1 and R3 each independently represent, at each occurrence when used herein, H or C1 to C5 alkyl; R2 represents halo; R4 and R5 each independently represent H; R6 represents -C(O)OR9; X represents CH2, O or S; R9 represents H or C1 to C5 alkyl; and, m is an integer from 1 to 6 inclusive.