LRRK2 Kinase Inhibitor Compounds for Potency and Selectivity Tuning
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Solution Overview
Problem
Current treatments for neurodegenerative diseases such as Parkinson's disease, Lewy body dementia, and CNS disorders associated with LRRK2 kinase activity are inadequate, and there is a need for compounds that can modulate LRRK2 kinase activity to address these conditions effectively.
Innovation Solution
Development of compounds, including pharmaceutically acceptable salts, stereoisomers, and prodrugs, capable of modulating LRRK2 kinase activity to treat neurodegenerative diseases, CNS disorders, and inflammatory diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for neurodegenerative diseases, then existing therapy options are available, but treatment effectiveness is inadequate
Solution Approach 1:
The patent employs parameter changes by modifying the chemical structure of LRRK2 kinase inhibitors to optimize their inhibitory potency and selectivity. The compounds feature specific structural parameters (substituents at positions R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93, R94, R95, R96, R97, R98, R99, R100) that can be varied to tune the inhibitor's affinity for LRRK2 kinase and its pharmacological properties, thereby improving treatment effectiveness while maintaining adequate modulation capability
2Reliability
If LRRK2 kinase activity is modulated to treat neurodegenerative diseases, then therapeutic benefits are achieved, but the complexity of compound development increases
Solution Approach 1:
The patent applies segmentation by dividing the LRRK2 kinase inhibitor into distinct structural modules or domains that can be independently optimized. The compound structure includes separable functional regions (such as the core heterocyclic system, substituent groups, and linker regions) that can be modified independently to achieve desired therapeutic effects while managing overall molecular complexity through modular design
Solution Approach 2:
The patent employs universality by designing LRRK2 kinase inhibitors with multi-functional structural features that can simultaneously achieve multiple therapeutic objectives. The compounds are structured to provide both LRRK2 kinase inhibition and additional pharmacological activities (such as blood-brain barrier penetration, metabolic stability, and reduced off-target effects) through integrated molecular design, thereby reducing the need for separate specialized compounds
Data Source
AI summary
Compounds having activity as inhibitors of LRRK2 kinase are provided. The compounds have Structure (I):or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, B, R1a, R1b, R2, and L are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of LRRK2 kinase are also provided.