Indole Derivative CRTH2 Antagonists with Metabolic Stability
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Solution Overview
Problem
Current CRTH2 receptor antagonists for treating allergic diseases such as asthma and atopic dermatitis have limitations in efficacy and stability, particularly in inhibiting the interaction between PGD2 and the CRTH2 receptor.
Innovation Solution
Development of indole derivatives with specific carboxylic acid substitutions that act as potent PGD2 antagonists, offering improved inhibitory activities and stability in liver microsomes, formulated as crystalline forms and pharmaceutical compositions for enhanced therapeutic effectiveness.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CRTH2 inhibitors (indolyl acetic acid derivatives, phenoxy acetic acid derivatives, pyrimidinyl acetic acid derivatives) are used, then CRTH2 receptor antagonism is achieved, but inhibitory activity and stability are insufficient
Solution Approach 1:
The patent modifies the chemical structure of CRTH2 inhibitors by introducing specific substituents at defined positions of the indole core (e.g., R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93, R94, R95, R96, R97, R98, R99, R100 positions), thereby optimizing both inhibitory activity and metabolic stability while maintaining CRTH2 receptor antagonism
Solution Approach 2:
The patent employs composite molecular structures combining indole core with various heterocyclic rings, aromatic groups, and functional substituents to create molecules that simultaneously achieve high CRTH2 binding affinity and resistance to metabolic degradation in liver microsomes
2Reliability
If CRTH2 antagonists are developed with improved inhibitory activity, then efficacy in vivo is enhanced, but stability in liver microsome may be compromised
Solution Approach 1:
The patent systematically varies chemical parameters including substituent types, positions, and configurations to identify structures that simultaneously achieve high in vivo efficacy and metabolic stability in liver microsomes, resolving the trade-off between activity and stability
3Reliability
If indole derivatives with carboxylic acid substitution at N atom are designed, then PGD2 antagonism at CRTH2 receptor is improved, but complexity of chemical structure increases
Solution Approach 1:
The patent introduces carboxylic acid substitution specifically at the N atom of the indole ring, a localized modification that enhances PGD2 antagonism at CRTH2 receptor while maintaining overall structural manageability through focused functionalization rather than widespread complexity
Data Source
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AI summary
The compounds of Formula (I) which can be used as CRTH2 receptor antagonists are provided. The compounds of Formula (I) can be used in the treatment and prevention of asthma, allergic rhinitis and atopic dermatitis, as well as other diseases mediated by prostaglandin D2 (PGD2) at the CRTH2 receptor.