Abl Kinase Inhibitor Formula I for Parkinson's Disease
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Solution Overview
Problem
Current c-Abl kinase inhibitors for treating Parkinson's disease, such as nilotinib, dasatinib, and ponatinib, have severe cardiovascular side effects and poor brain concentration due to being P-glycoprotein substrates, limiting their effectiveness and safety.
Innovation Solution
Development of a compound of Formula I, which is a potent Abl kinase inhibitor that effectively crosses the blood-brain barrier without causing cardiovascular side effects, characterized by specific structural groups (R1, R2, R3, and R4) and their pharmaceutically acceptable salts, allowing for high brain-to-plasma concentration ratios and a high therapeutic index.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing c-Abl kinase inhibitors (nilotinib, dasatinib, ponatinib) are used to treat Parkinson's disease, then Abl kinase inhibition is achieved, but severe cardiovascular side effects occur and brain concentration is poor due to P-glycoprotein substrate activity
Solution Approach 1:
The patent modifies the chemical structure of c-Abl kinase inhibitors by changing specific molecular parameters (substituting P-glycoprotein substrate groups with alternative structures) to achieve the desired effect of reducing cardiovascular side effects while maintaining therapeutic effectiveness. This involves altering the molecular formula and structural characteristics of the inhibitor compounds.
Solution Approach 2:
The patent introduces a new compound class that acts as an intermediary solution between the need for effective Abl kinase inhibition and the avoidance of P-glycoprotein-mediated cardiovascular toxicity. These novel compounds serve as mediators that achieve therapeutic goals without triggering the harmful transport mechanisms.
2Reliability
If existing c-Abl kinase inhibitors are used to treat Parkinson's disease, then Abl kinase inhibition is achieved, but brain concentration is poor due to P-glycoprotein substrate activity
Solution Approach 1:
The patent changes the molecular parameters of the inhibitor compounds to eliminate P-glycoprotein substrate activity. By modifying the chemical structure (changing molecular formula, removing specific functional groups), the compounds can now cross the blood-brain barrier effectively and achieve adequate brain concentration for treating Parkinson's disease.
3Reliability
If existing c-Abl kinase inhibitors are used, then Parkinson's disease treatment is attempted, but the therapeutic index is low due to severe side effects and poor brain concentration
Solution Approach 1:
The patent systematically changes the chemical parameters of the inhibitor compounds to simultaneously improve therapeutic index by eliminating cardiovascular side effects and enhancing brain penetration. The structural modifications result in a superior risk-benefit profile compared to existing inhibitors.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compound of Formula I effectively prevents neurodegeneration in Parkinson's disease models by inhibiting Abl kinase, showing significant protection of dopaminergic neurons and safety in cardiovascular parameters, with no undue effects on ECG parameters or heart rate, thus offering a safer treatment option compared to existing inhibitors.
Implementation Method 1
c-Abl is a non-receptor protein tyrosine kinase that is implicated in various cellular processes. c-Abl kinase inhibitors such as imatinib, nilotinib, dasatinib and ponatinib have been developed and marketed for clinical use.
Data Source
AI summary
The invention relates to a method of treating or preventing Parkinson's disease in a subject comprising administering a compound of Formula Iwherein, R1 is —NHC(O) C3-6 cycloalkyl and R2 is hydrogen;or R1 and R2 along with the carbon atoms to which they are attached form a six membered aromatic ring, wherein the ring is substituted with one or more groups selected from hydrogen, halogen and C1-6 alkyl;R3 and R4 are independently selected from group comprising hydrogen, halogen, C1-3 alkyl, OC1-3 alkyl, NO2, SC1-3 alkyl, C1-3 haloalkyl, OC1-3 haloalkyl, and SC1-3 haloalkyl; or a pharmaceutically acceptable salt thereof.