Phenylalanine-Based LAT1 Inhibitors for Selective Immune Modulation
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Solution Overview
Problem
Current therapies for inflammatory diseases, autoimmune diseases, graft-vs-host disease, and solid organ transplant rejection are inadequate, particularly due to the lack of effective small molecule inhibitors targeting the Large Amino Acid Transporter 1 (LAT1) to modulate immune response and metabolism.
Innovation Solution
Development of substituted phenylalanine derivatives that act as LAT1 inhibitors, which can be administered to patients to treat these conditions by targeting the LAT1 transporter and modulating immune cell metabolism.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies are used for inflammatory and autoimmune diseases, then treatment is provided, but the therapies are inadequate and lack effective LAT1 inhibition
Solution Approach 1:
The patent applies parameter changes by developing novel substituted phenylalanine derivative compounds with optimized chemical structures (Formulas 1-3) that specifically target LAT1. The compounds feature varied substituents (R1-R5 groups) that can be adjusted to optimize binding affinity and selectivity for LAT1, thereby improving therapeutic effectiveness while enabling specific targeting of immune cell metabolism without affecting normal cells.
2Adaptability or versatility
If LAT1 inhibition is achieved to modulate immune response, then novel therapy is provided, but selective regulation without affecting normal cells must be maintained
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features that confer selective affinity for LAT1 expressed on activated immune cells. The substituted phenylalanine derivatives (Formulas 1-3) contain specific functional groups and stereochemistry that match the binding pocket of LAT1 in immune cells, enabling localized inhibition of LAT1-mediated amino acid transport in pathogenic immune cells while sparing normal cells with lower LAT1 expression.
Solution Approach 2:
The patent applies partial action by achieving sufficient LAT1 inhibition in immune cells to modulate their metabolic functions and reduce pathogenic activity, without requiring complete inhibition of LAT1 in all cells. The compounds are designed to achieve therapeutic effects at concentrations that selectively inhibit LAT1 in activated immune cells while maintaining normal physiological functions in healthy cells.
3Adaptability or versatility
If small molecule LAT1 inhibitor is developed, then novel therapy is created, but improved drug-like properties must be achieved
Solution Approach 1:
The patent applies parameter changes by systematically optimizing the chemical parameters of the phenylalanine derivative compounds. The structures in Formulas 1-3 allow variation of key parameters including the substituent types (R1-R5), chain lengths, aromatic groups, and stereochemistry to optimize the balance between molecular complexity and drug-like properties such as solubility, stability, and bioavailability while maintaining LAT1 inhibitory activity.
Data Source
AI summary
Phenylalanine-based inhibitors of the Large Amino Acid Transporter 1 (LAT1) are disclosed. The compounds are useful in modulating the transcellular transport of substrates of LAT1 such as large neutral amino acids. The compounds are useful in immunomodulation therapies.