Substituted Purines Modulating PINK1 Kinase Activity
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Solution Overview
Problem
Current treatments for neurodegenerative diseases, mitochondrial diseases, cardiomyopathy, and fibrosis lack effective disease-modifying therapies, with PINK1 kinase activity being crucial for mitochondrial health and function but not adequately addressed by existing therapies.
Innovation Solution
Development of compounds with specific substitutions, such as methyl groups at R3 and R5 positions, which enhance PINK1 activity, improve toxicity profiles, oral bioavailability, and brain plasma penetration, facilitating better treatment of neurodegenerative diseases, mitochondrial diseases, cardiomyopathy, and fibrosis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapies are used for neurodegenerative diseases and mitochondrial diseases, then treatment options are limited, but PINK1 kinase activity is not adequately addressed
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical structures of purine compounds, specifically substituting groups at R3 and R5 positions with various alkyl, aryl, and heteroaryl groups to optimize PINK1 kinase activity while maintaining therapeutic effectiveness for neurodegenerative and mitochondrial diseases
Solution Approach 2:
The patent applies local quality by introducing specific substituents at particular positions (R3 and R5) of the purine core structure, where each substitution locally modifies the compound's interaction with PINK1 kinase to enhance activity and selectivity without affecting other therapeutic properties
2Power
If compound potency is increased through substitution, then PINK1 activity is enhanced, but toxicity may increase
Solution Approach 1:
The patent optimizes the balance between potency and toxicity by systematically varying substituent parameters at R3 and R5 positions, identifying specific combinations (such as methyl groups at both positions) that maximize PINK1 activation while maintaining acceptable safety profiles
Solution Approach 2:
The patent uses structure-activity relationship analysis to identify successful substituent patterns and applies these learned structures to design new compounds, copying the successful R3/R5 substitution pattern from lead compounds to optimize both potency and safety in subsequent generations of compounds
3Ease of manufacture
If oral bioavailability is improved, then treatment efficacy increases, but blood-brain barrier penetration may be reduced
Solution Approach 1:
The patent optimizes dual parameters of oral bioavailability and blood-brain barrier penetration by adjusting lipophilicity, molecular weight, and hydrogen bonding capacity through strategic substitution at R3 and R5, achieving compounds that satisfy both pharmacokinetic requirements for central nervous system therapeutic efficacy
Data Source
AI summary
The present disclosure is directed, in part, to substituted purines, or pharmaceutically acceptable salts thereof, represented by formula (VIII):for the treatment and/or prevention of neurodegenerative disease, mitochondrial disease, fibrosis, and/or cardiomyopathy.