N-alkylamides Upregulating Endothelial Nitric Oxide Synthase

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Solution Overview

Problem

Current treatments for cardiovascular disorders such as atherosclerosis, coronary artery disease, and cardiac insufficiency lack effective compounds that can safely and reliably upregulate endothelial nitric oxide synthase (eNOS) expression to increase NO levels, which is crucial for vascular health.

Innovation Solution

Development of N-alkylamides that modulate the transcription of endothelial nitric oxide synthase, specifically upregulating its expression to stimulate NO production, thereby addressing the need for pharmacologically active compounds that can treat these cardiovascular conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for cardiovascular disorders are used, then existing therapeutic options are available, but they lack effective compounds that can safely and reliably upregulate eNOS expression to increase NO levels

Engineering Contradiction:

ImproveeNOS upregulation effectivenessVSAvoidtherapeutic option availability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies molecular parameters by introducing specific heteroaryl groups (pyridine, pyrimidine, triazine, etc.) at the N-alkyl position of amide compounds. These structural parameter changes result in compounds that reliably upregulate eNOS expression, directly addressing the need for effective eNOS upregulation while maintaining therapeutic versatility

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite molecular structures by combining amide cores with diverse heteroaryl substituents and saturated linker groups. This composite approach generates a series of compounds with varying degrees of eNOS upregulation efficacy, providing both reliable effectiveness and therapeutic adaptability for different cardiovascular conditions

Inventive Principle:

Principle #40Composite materials

2Object-affected harmful factors

If eNOS expression is upregulated to increase NO levels, then vascular health is improved, but the safety and reliability of current treatment approaches are insufficient

Engineering Contradiction:

Improvevascular health improvementVSAvoidtreatment safety

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent develops small molecule amide compounds that act as transient but effective eNOS upregulators. These molecules provide the necessary therapeutic effect of increasing NO levels for vascular health improvement without the long-term safety concerns associated with other approaches, achieving both efficacy and safety

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The amide compounds with heteroaryl substituents serve as intermediary substances that mediate between the administered drug and the eNOS enzyme. These intermediaries safely and reliably upregulate eNOS expression, thereby improving vascular health through increased NO levels while maintaining treatment safety

Inventive Principle:

Principle #24Intermediary (Mediator)

3Adaptability or versatility

If N-alkylamides with heteroaryl groups are developed, then eNOS transcription can be modulated, but the structural complexity increases

Engineering Contradiction:

ImproveeNOS transcription modulation capabilityVSAvoidmolecular structure complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent segments the molecular structure into distinct functional modules: an amide core, saturated linker groups, and heteroaryl substituent modules. This segmentation allows systematic exploration of structure-activity relationships, enabling effective eNOS transcription modulation while managing structural complexity through modular design

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention creates a universal platform of amide compounds with heteroaryl groups that can modulate eNOS transcription across different cardiovascular conditions. The modular structure allows these compounds to serve multiple therapeutic functions, achieving versatile eNOS modulation without proportionally increasing structural complexity

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentEP1899321B1Heteroaryl-substituted amides comprising a saturated linker group, and their use as pharmaceuticals

Publication Date: 2011.12.28 SANOFI SA(FR)

AI summary

The present invention relates to N-alkylamides of the formula (I), in which A, Het, X, R1, R2 and R3 have the meanings indicated in the claims, which modulate the transcription of endothelial nitric oxide (NO) synthase and are valuable pharmacologically active compounds. Specifically, the compounds of the formula I upregulate the expression of the enzyme endothelial NO synthase and can be applied in conditions in which an increased expression of said enzyme or an increased NO level or the normalization of a decreased NO level is desired. The invention further relates to processes for the preparation of compounds of the formula I, to pharmaceutical compositions comprising them, and to the use of compounds of the formula I for the manufacture of a medicament for the stimulation of the expression of endothelial NO synthase or for the treatment of various diseases including cardiovascular disorders such as atherosclerosis, thrombosis, coronary artery disease, hypertension and cardiac insufficiency, for example.