Cyclic Urea Derivatives as C5a Receptor Modulators

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Solution Overview

Problem

Current treatments lack effective modulators for the C5a receptor (C5aR) to inhibit pathogenic events associated with elevated C5a levels, which are implicated in various inflammatory, autoimmune, and vascular disorders.

Innovation Solution

Development of cyclic urea derivatives as C5aR modulators, specifically antagonists, to target and inhibit C5aR activation, thereby addressing the pathogenic events associated with elevated C5a levels.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments are used, then existing therapeutic options are available, but they lack effective modulators for the C5a receptor to inhibit pathogenic events

Engineering Contradiction:

Improveeffectiveness of C5aR modulationVSAvoidavailability of C5aR modulators

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent segments the C5a receptor binding interface by designing cyclic urea derivatives that specifically target distinct regions of the C5aR binding pocket. The molecules are structured to interact with specific amino acid residues (e.g., Asp104, Ser105, Thr106) through hydrogen bonding and hydrophobic interactions, thereby achieving selective and effective C5aR modulation without requiring full C5a ligand structure

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent employs parameter changes by systematically varying the chemical structure of cyclic urea derivatives (changing R1, R2, R3, R4 substituents on the piperidine ring) to optimize binding affinity and selectivity for C5aR. This structure-activity relationship approach enables fine-tuning of the modulator properties to achieve reliable C5aR inhibition

Inventive Principle:

Principle #35Parameter changes

2Reliability

If C5aR is activated by C5a, then inflammatory responses are amplified, but this leads to tissue damage and pathological sequelae

Engineering Contradiction:

Improveimmune defense efficiencyVSAvoidtissue damage from inflammation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies preliminary anti-action by administering C5aR modulators (cyclic urea derivatives) before or during the onset of excessive C5a-mediated inflammation. The modulators pre-block the C5aR receptors, preventing C5a from binding and initiating the harmful inflammatory cascade, thereby protecting tissues while preserving necessary immune function

Inventive Principle:

Principle #9Preliminary anti-action

Solution Approach 2:

The patent converts the harmful effect of C5aR activation into a beneficial therapeutic outcome by using C5aR modulators that selectively inhibit pathogenic C5aR signaling while preserving complement-mediated pathogen clearance. The modulators transform the potentially damaging inflammatory response into a controlled, therapeutic anti-inflammatory effect

Inventive Principle:

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

Data Source

PatentUS11685729B2C5a receptor modulators

Publication Date: 2023.06.27 IDORSIA PHARMACEUTICALS LTD

AI summary

The present invention relates to derivatives of formula (I)wherein Ring A, W, X, Y, Z, R1, R2, R3 and R4 are as described in the description, 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 C5a receptor modulators.