Diarylalkylamine REV-ERB Antagonists Selectivity
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Solution Overview
Problem
Current REV-ERBα agonists and antagonists, such as GSK4112, SR9009, and SR9011, exhibit poor pharmacokinetic properties and lack selectivity for REV-ERBα, making them unsuitable for clinical use in treating circadian-related disorders and cancers, particularly those with the ErbB2 signature.
Innovation Solution
Development of novel diarylalkylamine compounds that act as selective REV-ERBα antagonists with improved bioavailability and potency, designed to modulate REV-ERB activity for cancer therapy, including breast and colon cancers, independently of p53 status.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current REV-ERBα agonists and antagonists (GSK4112, SR9009, SR9011) are used, then REV-ERBα activity is modulated, but pharmacokinetic properties are poor and selectivity is lacking
Solution Approach 1:
The patent applies parameter changes by systematically modifying the chemical structure of REV-ERBα modulators through variations in R1-R6 substituents, Ar and Ar' aromatic groups, and Y/X heteroatom configurations. These structural parameter changes aim to improve both selectivity for REV-ERBα and pharmacokinetic properties including bioavailability and metabolic stability, while maintaining the core diarylalkylamine scaffold that provides baseline activity.
2Reliability
If REV-ERBα agonists and antagonists are used for cancer therapy, then anti-proliferative activity is achieved, but poor pharmacokinetic properties limit clinical suitability
Solution Approach 1:
The patent employs parameter changes by optimizing molecular weight, lipophilicity, and hydrogen bonding capacity through systematic substitution patterns. These changes are designed to improve oral bioavailability and metabolic stability while preserving the anti-proliferative activity against cancers with altered circadian patterns, particularly those with ErbB2 signature.
Solution Approach 2:
The patent applies local quality by introducing specific functional groups at defined positions (R1-R6 substituents on aromatic rings) to enhance specific pharmacokinetic properties such as metabolic stability and membrane permeability, while maintaining the overall molecular architecture required for REV-ERBα binding and anti-cancer activity.
3Adaptability or versatility
If non-selective REV-ERB modulators are used, then broad REV-ERB activity is achieved, but lack of selectivity for REV-ERBα reduces therapeutic precision
Solution Approach 1:
The patent applies local quality by designing specific substituent patterns at key positions (particularly R1-R6 and the nature of Ar/Ar' groups) that create steric and electronic environments favoring selective binding to REV-ERBα over REV-ERBβ. This enables the compounds to differentiate between the two isoforms while maintaining adequate activity.
Solution Approach 2:
The patent employs asymmetry by introducing chiral centers and asymmetric substitution patterns on the aromatic rings that exploit the asymmetric binding pocket of REV-ERBα. This asymmetric design enhances selectivity by creating a better fit for REV-ERBα's specific amino acid residues while reducing affinity for REV-ERBβ.
Data Source
AI summary
The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts or solvates thereof:It further discloses a pharmaceutical composition comprising the compounds of Formula (I) and their uses as anti-proliferative and proapoptotic agents for cancer therapy.