Allosteric CRFR1 Antagonists for Selective p-Tau Modulation

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Solution Overview

Problem

Current treatments for neurological disorders such as Alzheimer's disease and psychiatric disorders related to corticotropin-releasing factor (CRF) lack selective and safe receptor antagonists, particularly for the CRFR1 receptor, which are effective in modulating p-Tau levels.

Innovation Solution

Development of allosteric CRFR1 receptor antagonists with specific chemical structures that selectively target the CRFR1 receptor, offering a greater safety profile and efficacy in modulating p-Tau levels.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If direct CRFR1 receptor antagonists are used, then CRF receptor blockade is achieved, but selectivity and safety profile are compromised

Engineering Contradiction:

ImproveCRF receptor blockade efficacyVSAvoidlack of selectivity and safety profile

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs allosteric modulators as intermediary compounds that bind to a site distinct from the orthosteric binding site of CRF. These allosteric compounds modulate receptor activity indirectly, providing greater selectivity for CRFR1 versus CRFR2 and improving the safety profile while maintaining therapeutic efficacy in neurological and psychiatric disorders

Inventive Principle:

Principle #24Intermediary (Mediator)

2Quantity of substance

If conventional CRF receptor antagonists are used, then broad CRF activity blockade is achieved, but p-Tau modulation efficacy is insufficient

Engineering Contradiction:

ImproveCRF receptor coverageVSAvoidp-Tau levels modulation

Core Design Contradiction:

Quantity of substanceVSReliability

Solution Approach 1:

The patent applies local quality by designing allosteric modulators with specific molecular structures (including various substituted phenyl, pyridyl, and heterocyclic groups) that selectively target CRFR1 in brain regions where p-Tau pathology occurs. This localized molecular design enables preferential modulation of p-Tau levels while maintaining broader CRF receptor coverage

Inventive Principle:

Principle #3Local quality

Data Source

PatentEP3510029B1Allosteric corticotropin-releasing factor receptor 1 (CRFR1) antagonists that decrease p-tau and improve cognition

Publication Date: 2025.11.05 RGT UNIV OF CALIFORNIA

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AI summary

In various embodiments novel allosteric antagonists of the CRFR1 receptor are provided. It discovered that allosteric CRFR1 receptor antagonists are effective to modulate p-Tau levels in Alzheimer's disease (AD) models.