Tropane Urea Derivatives Modulate 11βHSD1 Enzyme Activity

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Solution Overview

Problem

Current treatments for conditions such as metabolic syndrome, type 2 diabetes, cognitive decline, glaucoma, hypertension, and osteoporosis are limited by the inability to effectively modulate 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) activity, leading to inadequate management of glucocorticoid levels and associated symptoms.

Innovation Solution

Development of tropane urea derivatives that specifically modulate the activity of 11βHSD1, allowing for targeted regulation of glucocorticoid levels in various tissues, thereby addressing the underlying pathologies.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments are used for metabolic syndrome and diabetes, then general symptom management is achieved, but effective modulation of 11βHSD1 activity and glucocorticoid levels is inadequate

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidability to modulate 11βHSD1 activity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent develops tropane urea derivatives with modified chemical structures that specifically target 11βHSD1 enzyme parameters, changing the molecular characteristics to achieve effective inhibition of glucocorticoid conversion while maintaining selectivity for this specific enzyme pathway

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The tropane urea derivatives act as intermediary compounds that mediate between the 11βHSD1 enzyme and glucocorticoid levels, providing a specific molecular bridge to regulate enzyme activity and thereby control local glucocorticoid concentrations in target tissues

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If glucocorticoids are used to treat inflammatory conditions, then anti-inflammatory effects are achieved, but local glucocorticoid levels in tissues increase due to 11βHSD1 activity

Engineering Contradiction:

Improveinflammatory effectsVSAvoidlocal glucocorticoid levels

Core Design Contradiction:

Object-affected harmful factorsVSQuantity of substance

Solution Approach 1:

The patent converts the harmful effect of 11βHSD1-mediated glucocorticoid activation into a beneficial therapeutic outcome by developing inhibitors that block this conversion pathway, thereby reducing local glucocorticoid levels and associated side effects while maintaining the anti-inflammatory benefits of systemic glucocorticoid therapy

Inventive Principle:

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

3Reliability

If non-specific inhibitors of 11βHSD1 are used, then glucocorticoid conversion is inhibited, but specificity for the enzyme is reduced

Engineering Contradiction:

Improveinhibition of glucocorticoid conversionVSAvoidspecificity of enzyme inhibition

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The tropane urea derivatives exhibit local quality by demonstrating high specificity for 11βHSD1 enzyme through their unique molecular structure, allowing selective inhibition of this particular enzyme isoform while sparing other dehydrogenase enzymes and reducing off-target effects

Inventive Principle:

Principle #3Local quality

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The tropane urea derivatives effectively modulate 11βHSD1 activity, providing therapeutic benefits for metabolic syndrome, type 2 diabetes, cognitive decline, glaucoma, hypertension, and osteoporosis by regulating glucocorticoid levels, improving insulin sensitivity, reducing intraocular pressure, and protecting against bone resorption.

Implementation Method 1

11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) locally catalyzes the conversion of inactive glucocorticoids (cortisone in humans) to active glucocorticoids (cortisol in humans) in different tissues and organs

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Data Source

PatentEP2046791B1Urea derivatives of tropane, their preparation and their therapeutic application

Publication Date: 2010.03.24 SANOFI AVENTIS SA

AI summary

The invention relates to compounds of the formula (I): in which R1a, R1b, R1c, R1d, R2a, R2b, R3, R4, p, r and X are as defined in the description. Preparation process and therapeutic application.