Indole-1-acetic acid derivatives for CRTH2 antagonist activity
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Solution Overview
Problem
Current compounds targeting the CRTH2 receptor for treating allergic diseases and inflammatory conditions mediated by PGD2 have suboptimal pharmacokinetic profiles and potency in vivo, despite showing promise in vitro.
Innovation Solution
Development of novel indole-1-acetic acid derivatives with specific structural modifications, such as replacing the methylsulfonyl group with a SO2R group at the benzene ring, which enhance both in vitro whole blood eosinophil shape change potency and in vivo inhibition of DK-PGD2-induced blood eosinophilia, improving their pharmacokinetic profile.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current CRTH2 receptor compounds are used, then in vitro activity is shown, but in vivo potency and pharmacokinetic profile are suboptimal
Solution Approach 1:
The patent applies parameter changes by systematically modifying the R1 substituent on the indole nitrogen and R2 substituent on the benzene ring of the indole-1-acetic acid core structure. These structural parameter changes optimize both in vivo potency (through improved CRTH2 receptor binding) and pharmacokinetic properties (through enhanced metabolic stability and oral bioavailability), resolving the contradiction between in vitro activity and in vivo performance.
2Manufacturing precision
If structural modifications are made to enhance potency, then in vitro eosinophil shape change potency improves, but complexity of compound structure increases
Solution Approach 1:
The patent applies local quality by introducing specific substituents at targeted positions (R1 on indole nitrogen and R2 on benzene ring) rather than modifying the entire molecule. This localized structural modification approach enhances eosinophil shape change potency through improved receptor interaction while maintaining overall structural simplicity and avoiding unnecessary complexity in other parts of the molecule.
Data Source
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AI summary
Compounds of general formula (I) wherein R is phenyl optionally substituted with one or more halo substituents ; and their pharmaceutically acceptable salts, hydrates, solvates, complexes or prodrugs are useful in orally administrable compositions for the treatment of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis.