Triazine 11-beta-HSD1 Inhibitors with Localized Selectivity

Solution Overview

Problem

Current treatments for metabolic disorders associated with 11-beta-hydroxysteroid dehydrogenase type I (11-beta-HSD1) activity are limited, as existing inhibitors often have off-target effects or are not selective enough to effectively manage conditions like diabetes, obesity, and cardiovascular diseases.

Innovation Solution

Development of aryl and heterocyclyl compounds that specifically inhibit 11-beta-HSD1 activity, providing a therapeutic option for treating multiple diseases related to this enzyme, including diabetes, obesity, and cardiovascular diseases, by administering a therapeutically effective amount of these compounds alone or in combination with other agents.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing inhibitors are used to treat metabolic disorders, then some therapeutic effect is achieved, but off-target effects occur and selectivity is insufficient

Engineering Contradiction:

Improvetherapeutic effectVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing inhibitors with specific molecular features (aryl and heterocyclyl groups at defined positions) that confer selectivity for 11β-HSD1 over other enzymes. The structural modifications at specific locations of the molecule create localized interactions that enhance binding affinity and selectivity for the target enzyme, reducing off-target effects while maintaining therapeutic efficacy.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying structural parameters of the inhibitor molecules (substituents R1-R6, ring structures, stereochemistry) to optimize selectivity and potency. By changing these molecular parameters, the invention achieves improved discrimination between 11β-HSD1 and other enzymes, thereby reducing harmful off-target effects while preserving the desired therapeutic action.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If existing inhibitors are used to treat metabolic disorders, then some therapeutic effect is achieved, but selectivity is not sufficient

Engineering Contradiction:

Improvetherapeutic effectVSAvoidselectivity

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The patent applies local quality by designing inhibitors with specific molecular features (aryl and heterocyclyl groups at defined positions) that confer selectivity for 11β-HSD1 over other enzymes. The structural modifications at specific locations of the molecule create localized interactions that enhance binding affinity and selectivity for the target enzyme, reducing off-target effects while maintaining therapeutic efficacy.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying structural parameters of the inhibitor molecules (substituents R1-R6, ring structures, stereochemistry) to optimize selectivity and potency. By changing these molecular parameters, the invention achieves improved discrimination between 11β-HSD1 and other enzymes, thereby reducing harmful off-target effects while preserving the desired therapeutic action.

Inventive Principle:

Principle #35Parameter changes

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 compounds effectively inhibit 11-beta-HSD1 activity, offering a viable strategy for preventing or treating metabolic disorders such as diabetes, obesity, and cardiovascular diseases with improved selectivity and reduced side effects compared to existing treatments.

Implementation Method 1

The compounds effectively inhibit 11-beta-HSD1 activity, offering a viable strategy for preventing or treating metabolic disorders

Methodology Applied

Scientific EffectEnzyme inhibition: Enzyme

Data Source

PatentUS7834178B2Triazine 11-beta hydroxysteroid dehydrogenase type 1 inhibitors

Publication Date: 2010.11.16 BRISTOL MYERS SQUIBB CO

AI summary

Novel compounds are provided which are 11-beta-hydroxysteroid dehydrogenase type I inhibitors. 11-beta-hydroxysteroid dehydrogenase type I inhibitors are useful in treating, preventing, or slowing the progression of diseases requiring 11-beta-hydroxysteroid dehydrogenase type I inhibitor therapy. These novel compounds have the structure:or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 are defined herein.