Spirocyclic MAGL Inhibitors With Improved Cellular Engagement

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Solution Overview

Problem

Existing MAGL inhibitors lack improved physicochemical properties such as cellular activity and lipophilic efficiency, limiting their effectiveness in treating conditions like cancer and other pathologies.

Innovation Solution

Development of compounds with specific structural features, including a 6-membered aromatic or heteroaromatic ring system, various functional groups, and optional fusion with cycloalkyl rings, to enhance MAGL inhibition and improve ADME properties.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing MAGL inhibitors are used, then they can inhibit MAGL enzyme activity, but they lack improved physicochemical properties such as cellular activity and lipophilic efficiency

Engineering Contradiction:

ImproveMAGL inhibition efficacyVSAvoidphysicochemical properties (cellular activity and lipophilic efficiency)

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent applies parameter changes by systematically modifying molecular parameters including lipophilicity (logP), molecular weight, and structural features to optimize the balance between MAGL inhibition efficacy and cellular activity. The compounds are designed with specific parameter ranges to achieve improved lipophilic efficiency while maintaining target engagement.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite molecular structures combining aromatic rings (phenyl, pyridyl, benzodioxole), heterocycloalkyl groups, and various functional moieties to create compounds with optimized physicochemical properties. These composite structures achieve both high MAGL binding affinity and improved cellular permeability.

Inventive Principle:

Principle #40Composite materials

2Reliability

If MAGL inhibitors are developed to treat cancer, then they can interfere with fatty acid network promoting cancer pathogenesis, but they need to achieve high cellular target engagement and high lipophilic efficiency simultaneously

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidcompound structure complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies local quality by introducing specific functional groups at particular positions within the molecular structure to achieve localized interactions with the MAGL enzyme. This includes placing electron-withdrawing or electron-donating groups, heteroatoms, and substituents at strategic positions to optimize both binding affinity and physicochemical properties without requiring overall structural complexity.

Inventive Principle:

Principle #3Local quality

3Measurement precision

If compounds with improved cellular activity are designed, then target engagement increases, but lipophilic efficiency may be compromised

Engineering Contradiction:

Improvecellular target engagementVSAvoidlipophilic efficiency

Core Design Contradiction:

Measurement precisionVSQuantity of substance

Solution Approach 1:

The patent applies partial action by introducing moderate lipophilic character through specific substituents and ring systems that provide sufficient membrane permeability and cellular uptake without excessive lipophilicity that would compromise solubility and metabolic stability. This balanced approach achieves optimal cellular target engagement with maintained lipophilic efficiency.

Inventive Principle:

Principle #16Partial or excessive action

Data Source

PatentEP4696690A1Spirocyclic MAGL inhibitors

Publication Date: 2026.02.18 LEIDEN UNIVERSITY

Figure 1A~1C
Figure 2A~2C
Figure 3

AI summary

This invention relates to compound of formula I that are useful as inhibitors, in particular as inhibitors of monoacylglycerol lipase (MAGL). The invention also relates to uses of said compounds.