S1P and ATX Modulating Agents for Demyelination Treatment
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Solution Overview
Problem
Current treatments for demyelination disorders, such as multiple sclerosis, are limited in effectiveness, with immunoregulatory drugs merely postponing disability onset and offering few options for demyelination caused by non-autoimmune factors, highlighting the need for new therapeutic approaches.
Innovation Solution
Development of agents that modulate S1P and/or ATX, including S1P4 antagonists and ATX inhibitors, represented by a specific compound formula, to target S1P receptors and ATX activity, potentially promoting myelination or remyelination and reducing chronic pain.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunoregulatory drugs are used to treat demyelination disorders, then the onset of disability is postponed, but the effectiveness is limited and no new therapeutic options are provided
Solution Approach 1:
The patent segments the treatment approach by targeting specific molecular pathways (S1P receptors and ATX enzyme) rather than using broad immunoregulatory mechanisms. This allows for more precise and effective treatment of demyelination disorders while providing new therapeutic options beyond conventional immunosuppressants.
Solution Approach 2:
The patent introduces S1P modulating agents as intermediary compounds that specifically regulate S1P signaling pathways and ATX activity. These agents act as mediators between the immune system and myelin-producing cells, enabling more effective and versatile treatment approaches for demyelination disorders.
2Reliability
If current immunoregulatory treatments are used, then some disease progression is slowed, but they offer few options for demyelination caused by non-autoimmune factors
Solution Approach 1:
The patent develops S1P modulating agents with multi-functional capabilities that address both autoimmune and non-autoimmune demyelination mechanisms. By targeting the conserved S1P signaling pathway and ATX enzyme, these agents provide versatile treatment options applicable across different etiologies of demyelination disorders.
Solution Approach 2:
The patent employs parameter changes by modulating S1P receptor activity and ATX enzyme function through chemically diverse compounds with varying potencies and selectivities. This allows optimization of treatment for different disease causes and severities, enhancing both reliability and versatility of the therapeutic approach.
3Reliability
If S1P receptor activity is modulated to promote myelination, then oligodendrocyte progenitor cell differentiation is enhanced, but selective targeting of specific S1P receptors is required to avoid side effects
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular features that confer selectivity for particular S1P receptor subtypes (e.g., S1P1, S1P4) or the ATX enzyme. This enables targeted modulation of myelination-promoting pathways while minimizing effects on other S1P-mediated processes, thus enhancing reliability without excessive complexity.
Data Source
AI summary
Compounds of formula (I) wherein: X is —O—, —S(O)r—, —CH2—, or —NR—, wherein r is 0, 1, or 2; X1, X2, and X5 are each independently CR7 or N; one of X3 or X4 is C and is attached by a single bond to -L-, and the other is CR7 or N, provided that no more than three of X1, X2, X3, X or X5 are N; Ring A is monocyclic C5-6scycloalkyl or a 5- to 6-membered monocyclic heterocyclyl comprising from 1 to 5 heteroatoms independently selected from N, S, or O; wherein Ring A is further optionally substituted with from 1 to 3 R4; provided that Ring A is not morpholinyl, thiomorpholinyl or tetrahydro-2H-pyranyl; L is a bond, —O—, —NR—, —S(O)n—, —CH2—, or —C(O)—, wherein n is 0, 1, or 2; 1 2 L1 is an C1-8alkylene, C3-scycloalkylene, —CH2-L2-, or a 3- to 8-membered heterocyclylene comprising 1 to 5; R1 is C6-20alkyl or a monocyclic C3-8cycloalkyl; wherein said C3-8cycloalkyl is substituted with at least one R6 and may be optionally substituted with from 1 to 5 additional R6 substituents, wherein R6 for each occurrence is independently selected; and R2 is —C(O)OR3, —C(O)N(R3)—S(O)2R3, —S(O)2OR3, —C(O)NHC(O)R3, —Si(O)OH, —B(OH)2, —N(R3)S(O)2R3, —S(O)2N(R3)2, —O—P(O)(OR3)2, or —P(O)(OR3)2, —CN, —S(O)2NHC(O)R3, —C(O)NHS(O)2R3, —C(O)NHOH, —C(O)NHCN, —CH(CF3)OH, —C(CF3)2OH, or a selected heteroaryl or heterocyclyl; and pharmaceutically acceptable salts thereof, can modulate the activity of one or more SIP receptors and/or the activity of autotaxin (ATX).