Pyrimidine Derivatives as Dual EP2 EP4 Antagonists
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Solution Overview
Problem
Current treatments for cancer, particularly those involving immune modulation, face challenges in effectively targeting the tumor microenvironment due to the immuno-suppressive effects of PGE2 signaling through EP2 and EP4 receptors, which promote tumor growth and immune evasion.
Innovation Solution
Development of novel pyrimidine derivatives that act as dual antagonists of the EP2 and EP4 receptors, modulating the immune response to reactivate the immune system within tumors, potentially used in combination with chemotherapy, radiotherapy, or immunotherapy for various cancer types.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If COX2 inhibitors are used to block PGE2 production, then tumor growth is inhibited, but cardiovascular side effects occur
Solution Approach 1:
The patent segments the PGE2 signaling pathway by selectively blocking EP2 and EP4 receptors while leaving COX enzyme activity intact. This allows PGE2 production to continue for potential beneficial effects while preventing tumor-promoting signaling through specific receptor antagonism, thereby avoiding cardiovascular side effects associated with COX inhibition
Solution Approach 2:
The invention extracts and targets only the harmful PGE2 signaling component through selective EP2/EP4 receptor antagonism, separating it from the broader COX enzyme inhibition approach. This selective extraction allows treatment of the specific pathological pathway without the systemic cardiovascular effects of non-selective COX inhibition
2Reliability
If PGE2 signaling through EP2 and EP4 receptors is blocked, then immune response is reactivated, but tumor microenvironment complexity increases
Solution Approach 1:
The dual antagonist compounds exhibit multi-functionality by simultaneously blocking both EP2 and EP4 receptors with a single molecule. This universal approach addresses multiple PGE2-mediated immunosuppressive pathways concurrently, simplifying treatment compared to using separate agents for each receptor while effectively reactivating immune response
Solution Approach 2:
The patent introduces dual antagonist compounds as intermediary substances that mediate between the complex tumor microenvironment and the immune system. These compounds specifically intercept PGE2 signaling at the EP2/EP4 receptor level, translating the complex microenvironmental signals into controlled immune reactivation without requiring direct manipulation of the entire microenvironment
Data Source
AI summary
The present invention relates to pyrimidine derivatives of formula (I)wherein (R1)n, R3, R4a, R4b, R5a, R5b and Ar1 are as described in the description and their use in the treatment of cancer by modulating an immune response comprising a reactivation of the immune system in the tumor. The invention further relates to novel benzofurane and benzothiophene derivatives of formula (II) and their use as pharmaceuticals, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as modulators of the prostaglandin 2 receptors EP2 and/or EP4.