Spirocycle Compounds Modulating MAGL and ABHD6 Enzymes
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Solution Overview
Problem
Current treatments for pain, epilepsy/seizure disorders, multiple sclerosis, neuromyelitis optica, Tourette syndrome, Alzheimer's disease, and abdominal pain associated with irritable bowel syndrome lack effective modulators for MAGL and ABHD6, enzymes involved in lipid mediator regulation.
Innovation Solution
Development of compounds, such as those represented by Formula (I) and (Ia), which act as modulators or inhibitors of MAGL and/or ABHD6, capable of inhibiting these enzymes to treat various diseases by regulating lipid mediators.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for pain and neurological disorders, then existing therapeutic options are maintained, but effective modulators for MAGL and ABHD6 enzymes are lacking
Solution Approach 1:
The patent applies parameter changes by systematically varying molecular parameters (R1, R2, R3, R4, R5, R6, R7 substituents; n, m, p values) to optimize enzyme modulation. This includes changing chemical structure parameters to achieve selective inhibition of MAGL and/or ABHD6 enzymes, thereby improving therapeutic effectiveness for pain and neurological disorders while addressing the lack of effective modulators
Solution Approach 2:
The patent applies local quality by introducing specific functional groups at different positions (R1-R7) of the spirocycle core structure. Each substituent position provides localized chemical properties that can be independently optimized to enhance binding affinity and selectivity for target enzymes, enabling precise modulation without affecting other therapeutic properties
2Adaptability or versatility
If spirocycle compounds with multiple variable substituents are developed, then enzyme modulation capability is improved, but structural complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the molecule into a core spirocycle structure and multiple independent substituent positions (R1-R7). This modular approach allows each position to be optimized independently for specific enzyme targets while maintaining a consistent core framework, thereby improving enzyme modulation capability without proportionally increasing overall molecular complexity
Solution Approach 2:
The patent applies universality by designing a spirocycle core structure that can serve multiple functions through different substituent combinations. The same core structure with varying R groups can modulate different enzymes (MAGL, ABHD6) and potentially address multiple indications (pain, epilepsy, multiple sclerosis), reducing the need for entirely separate molecular designs for different therapeutic goals
Data Source
AI summary
Provided herein are spirocycle compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful as modulators of MAGL and/or ABHD6. Furthermore, the subject compounds and compositions are useful for the treatment of pain.