GPR65 Modulator Compounds for Selectivity and Oral Exposure
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Solution Overview
Problem
Current small molecule GPR65 modulators lack enhanced activity, in vitro selectivity, and oral pharmacokinetic profiles necessary for effective therapeutic intervention in disorders such as cancer and autoimmune diseases.
Innovation Solution
Development of novel compounds capable of modulating GPR65, including specific substituents on a tricyclic structure, to enhance activity and selectivity, and improve oral pharmacokinetic profiles.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current small molecule GPR65 modulators are used, then basic GPR65 modulation is achieved, but enhanced activity, in vitro selectivity, and oral pharmacokinetic profiles are lacking
Solution Approach 1:
The patent applies local quality by introducing specific substituents at defined positions on the tricyclic core structure. Different substituents (halo, cyano, hydroxyl, alkyl, heterocyclic groups) are placed at specific locations to optimize local interactions with the GPR65 binding pocket, thereby enhancing both activity and selectivity simultaneously
Solution Approach 2:
The patent employs parameter changes by systematically varying structural parameters of the tricyclic compounds including substituent types, positions, and combinations. This allows optimization of pharmacokinetic parameters (oral bioavailability, metabolic stability) and pharmacodynamic parameters (potency, selectivity) to achieve enhanced overall performance
2Reliability
If GPR65 modulation is achieved in tumour-associated macrophages, then anti-inflammatory phenotype is promoted, but tumour detection by immune system is evaded
Solution Approach 1:
The patent applies inversion by designing compounds that activate GPR65 in tumour-associated macrophages to promote anti-inflammatory phenotype, while simultaneously blocking GPR65 activation in other immune cells to prevent tumour evasion. This differential modulation strategy reverses the harmful effect by creating opposing effects in different cell types
Solution Approach 2:
The patent uses GPR65 as an intermediary target to indirectly modulate tumour-immune interactions. By targeting GPR65, the compounds mediate effects on macrophage polarization and cytokine production, which in turn affects tumour visibility to the immune system without directly interacting with tumour cells
3Reliability
If GPR65 acts through ICER in CD4+ T cells, then Th17 differentiation is promoted, but pathogenicity in autoimmune disease is increased
Solution Approach 1:
The patent applies parameter changes by modifying the structural parameters of GPR65 modulators to achieve selective activation or inhibition in different cell contexts. By adjusting substituent patterns on the tricyclic core, the compounds can modulate GPR65 activity in CD4+ T cells to control Th17 differentiation and reduce autoimmune pathogenicity
Data Source
AI summary
One aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, (Formula (I)) wherein: ring B is: a monocyclic aromatic group; or a monocyclic or bicyclic heteroaromatic group, each of which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO2-alkyl, wherein said aryl, heteroaryl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, haloalkoxy and alkoxy; a is a single bond, Z is NR7, b is a double bond and Y is CR8; or a is double bond, Z is N, b is a single bond and Y is CR8R9; X is selected from O and S; R6 and R7 are each independently selected from H, alkyl, cycloalkyl and hydroxyalkyl. R8 and R9 are each independently selected from H, F, alkyl, and haloalkyl; and Ra and Rb are each independently selected from H and alkyl. Further aspects of the invention relate to compounds of formula (I) for use as a medicament, particularly in the field of immuno-oncology, immunology, and related applications.