Tetrahydropyrido-pyridine C5a Receptor Modulators for AMD

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Solution Overview

Problem

Current medical therapies are inadequate for treating dry age-related macular degeneration (AMD) and many patients with neovascular AMD progress to legal blindness despite treatment with anti-VEGF agents, highlighting the need for effective therapeutic agents targeting complement-mediated diseases.

Innovation Solution

Development of tetrahydropyrido-pyridine and tetrahydropyrido-pyrimidine compounds that modulate C5a receptor activation, acting as high-affinity antagonists to inhibit C5a receptor-mediated signal transduction, which can be used in pharmaceutical compositions to treat inflammatory and immune system disorders, including AMD.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current medical therapies are used for treating dry AMD, then treatment is provided, but therapeutic effectiveness is inadequate and patients progress to legal blindness

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoiddisease progression to blindness

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces C5a receptor modulators as intermediary compounds that mediate between the complement system and inflammatory responses. These compounds specifically target the C5a receptor to block harmful signaling pathways, providing a mechanistic bridge that addresses the inadequacy of current therapies by directly interfering with the complement-mediated inflammatory cascade in AMD

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the therapeutic parameter from general anti-VEGF activity to specific C5a receptor modulation. By developing compounds with defined chemical structures (Formula I and Formula II) that specifically bind to and modulate the C5a receptor, the therapy shifts from non-specific to targeted parameter control, improving reliability while reducing harmful effects of uncontrolled inflammation

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If anti-VEGF agents are used to treat neovascular AMD, then vascular leakage is reduced, but patients still progress to legal blindness

Engineering Contradiction:

Improvevascular leakageVSAvoidprevention of blindness progression

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent segments the therapeutic approach by targeting a different pathway (C5a receptor) rather than relying solely on anti-VEGF mechanisms. This segmentation of the complement system targeting allows for addressing inflammatory components that anti-VEGF agents do not control, thereby improving the reliability of preventing blindness progression while maintaining the benefits of vascular leakage reduction

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The C5a receptor modulators perform preliminary anti-action by blocking the chemotactic and inflammatory effects of C5a before these signals can recruit additional inflammatory cells and exacerbate tissue damage. This preemptive blocking of the complement cascade occurs upstream of the final damaging events, providing enhanced protection against blindness progression

Inventive Principle:

Principle #9Preliminary anti-action

Data Source

PatentEP2734521B1Tetrahydropyrido-pyridine and tetrahydropyrido-pyrimidine compounds and use thereof as c5a receptor modulators

Publication Date: 2017.05.10 NOVARTIS AG

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AI summary

The present invention provides a compound of formula I: (I) a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.