HtrA1 Inhibitor Compounds for Retinal Tissue Protection

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Solution Overview

Problem

Current treatments for age-related macular degeneration, particularly dry AMD, lack effective prevention of vision loss and progression to retinal tissue atrophy, with no established therapies for dry form, and existing treatments focus mainly on wet AMD.

Innovation Solution

Development of novel serine protease HtrA1 inhibitors in the form of specific organic compounds that target and inhibit HtrA1, potentially protecting retinal tissue by reducing degradation of extracellular matrix proteins, thereby addressing the pathophysiological progression of AMD.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments (anti-VEGF antibodies and traps) are used for wet AMD, then vision loss can be managed, but there are no effective treatments for preventing vision loss in dry AMD and preventing progression to geographic atrophy

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidapplicability to different AMD forms

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The HtrA1 inhibitor compounds are designed to have broad therapeutic applicability across multiple AMD forms (both dry and wet AMD) and other HtrA1-mediated diseases, replacing the need for form-specific treatments with a universal mechanism that addresses the common underlying pathology of HtrA1-mediated ECM degradation

Inventive Principle:

Principle #6Universality (Multi-functionality)

2Reliability

If HtrA1 protein levels are increased (as seen in AMD patients with risk alleles), then the disease progression is accelerated, but inhibiting HtrA1 is necessary to prevent ECM degradation

Engineering Contradiction:

Improveprotection of retinal tissueVSAvoidHtrA1-mediated degradation of ECM proteins

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The invention converts the harmful HtrA1 protease activity into a therapeutic target by designing specific inhibitors that block this activity. The compounds transform the disease-causing mechanism (HtrA1-mediated ECM degradation) into a treatable condition by selectively inhibiting the protease while preserving other physiological functions

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

3Adaptability or versatility

If novel HtrA1 inhibitor compounds are developed, then therapeutic options for AMD are expanded, but the complexity of drug development and clinical validation increases

Engineering Contradiction:

Improvetherapeutic options availableVSAvoidcomplexity of compound development

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent segments the HtrA1 inhibitor development into distinct chemical series and structural classes (compounds of formula I with various R1, R2, R3, R4, R5, R6, R7 substituents), allowing systematic optimization and evaluation of different molecular frameworks to identify the most effective and safe candidates

Inventive Principle:

Principle #1Segmentation

Data Source

PatentEP3262026B1New trifluoromethylpropanamide derivatives

Publication Date: 2020.03.18 F HOFFMANN LA ROCHE & CO AG

AI summary

The invention provides novel compounds having the general formula (I) wherein R1, R2, R3, R4, R5, R6 and R7 are as described herein, compositions including the compounds and methods of using the compounds.