Spirocyclic TPH1 Inhibitors for Peripheral Serotonin Control
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Solution Overview
Problem
Current TPH1 inhibitors, such as p-chlorophenylalanine, affect central serotonin levels and have central nervous system side effects, and there is a need for selective reduction of intestinal serotonin levels to treat serotonin-associated diseases without impacting brain serotonin levels.
Innovation Solution
Development of a TPH-inhibiting compound of Formula I, which selectively inhibits TPH1 in the periphery, reducing intestinal serotonin levels without affecting central serotonin production, thereby treating or preventing diseases associated with peripheral serotonin dysregulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If current TPH1 inhibitors like p-chlorophenylalanine are used to reduce intestinal serotonin levels, then peripheral serotonin levels are lowered, but central serotonin levels are also affected causing CNS side effects
Solution Approach 1:
The invention segments the inhibition action to be selective for TPH1 isoform in peripheral tissues while sparing TPH2 in the CNS. This is achieved through specific molecular structure design (Formula I compounds with particular substituent patterns) that confers isoform selectivity, allowing peripheral serotonin reduction without affecting central serotonin production, thus eliminating CNS side effects
Solution Approach 2:
The patent introduces a selective inhibitor compound as an intermediary that specifically targets peripheral TPH1 enzyme. The compound acts as a mediator between the therapeutic goal (reducing peripheral serotonin) and the constraint (avoiding CNS effects), achieving selective inhibition through its molecular structure that preferentially binds to TPH1 over TPH2
2Quantity of substance
If selective TPH1 inhibitors are developed to reduce intestinal serotonin, then peripheral serotonin levels are lowered without affecting brain serotonin, but this requires highly specific molecular design
Solution Approach 1:
The invention applies local quality by introducing specific substituent groups at particular positions on the core molecular structure (as defined in Formula I). These localized structural modifications (R1-R6 substituents at specific ring positions) confer TPH1 selectivity without requiring complete redesign of the entire molecule, thus achieving high selectivity with controlled structural complexity
Solution Approach 2:
The patent achieves selective inhibition by changing molecular parameters such as substituent types, positions, and steric properties in the compound structure. By systematically varying these parameters (different R groups, ring sizes, substitution patterns), the invention optimizes binding affinity for TPH1 while maintaining reasonable molecular complexity
Data Source
AI summary
The present invention is directed to spirocyclic compounds which are inhibitors of tryptophan hydroxylase (TPH), particularly isoform 1 (TPH1), that are useful in the treatment of diseases or disorders associated with peripheral serotonin including, for example, gastrointestinal, cardiovascular, pulmonary, inflammatory, metabolic, and low bone mass diseases, as well as serotonin syndrome, and cancer.