Pyrimidinone Agonists for APJ Receptor Potency and Stability

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Solution Overview

Problem

There is a continued need for effective agonists of the APJ receptor to treat cardiovascular conditions such as chronic systolic and diastolic heart failure, as well as other conditions like obesity and diabetes, where existing small molecule agonists have limitations in potency and stability.

Innovation Solution

The development of specific compounds, represented by Formula I and Formula II, which are designed to activate the APJ receptor, offering improved potency and stability through various substituents and structural modifications, allowing for effective treatment of cardiovascular conditions and other diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing small molecule agonists are used to activate the APJ receptor, then cardiovascular conditions can be treated, but the potency and stability are insufficient

Engineering Contradiction:

Improvepotency and stability of agonistVSAvoideffectiveness in treating various cardiovascular conditions

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by systematically modifying chemical parameters of the small molecule agonists, including substituent types (R1, R2, R3, R4 groups), ring structures, and molecular weight ranges (150-500 Da). These parameter modifications optimize both potency (IC50 values) and stability while maintaining the ability to treat various cardiovascular conditions through the APJ receptor activation mechanism

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite molecular structures combining heterocyclic rings (pyrimidinone, pyridine, triazole), aromatic groups, and various substituent patterns to create composite agonist molecules. This composite approach enhances both reliability (potency and stability) and adaptability (versatility in treating different cardiovascular conditions) by leveraging synergistic effects of multiple structural components

Inventive Principle:

Principle #40Composite materials

2Reliability

If apelin peptides are used as agonists, then high potency is achieved, but the plasma half-life is brief

Engineering Contradiction:

Improvein vitro affinity to APJ receptorVSAvoidplasma half-life

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent substitutes the peptide-based agonist system with a small molecule chemical system. This replacement eliminates the inherent instability and brief half-life of peptides while maintaining high affinity for the APJ receptor through optimized molecular structures featuring heterocyclic cores and tailored substituent patterns that resist metabolic degradation

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The patent changes fundamental parameters of the agonist molecule by transitioning from peptide chemistry to small molecule chemistry, with molecular weights between 150-500 Da, specific heterocyclic ring structures, and controlled lipophilicity. These parameter changes achieve both high in vitro affinity and improved in vivo stability with extended duration of action compared to apelin peptides

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11807624B2Substituted pyrimidinones as agonists of the APJ receptor

Publication Date: 2023.11.07 AMGEN INC

AI summary

Compounds of Formula I and Formula II, pharmaceutically acceptable salts thereof, stereoisomers of any of the foregoing, or mixtures thereof are agonists of the APJ Receptor and may have use in treating cardiovascular and other conditions. Compounds of Formula I and Formula II have the following structures: Figure I and Figure II where the definitions of the variables are provided herein.