Fused Triazole APJ Receptor Agonists for Heart Failure
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Solution Overview
Problem
There is a need for effective small molecule agonists of the APJ receptor to treat cardiovascular and other conditions, as existing compounds have limitations in terms of potency and stability, particularly for conditions like chronic heart failure and hypertension.
Innovation Solution
The development of a compound of Formula I, which includes a triazole ring system with specific substituents and ring structures, designed to activate the APJ receptor, potentially offering improved potency and stability as a therapeutic agent for cardiovascular conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing small molecule agonists are used to activate the APJ receptor, then cardiovascular conditions can be treated, but the compounds have limitations in terms of potency and stability
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of small molecule agonists through specific substitutions and fusion ring designs. The compounds feature a triazole ring fused to a B ring (5-10 membered saturated or partially unsaturated ring containing 0-3 heteroatoms) and a C ring (phenyl, heteroaryl, heterocyclyl, or cycloalkyl), with various substituent options at defined positions. This structural parameter optimization aims to simultaneously improve both potency and stability of the APJ receptor agonists
Solution Approach 2:
The patent employs composite material principles by creating fused ring systems that combine multiple structural elements. The core structure integrates a triazole ring fused to a B ring and further fused to a C ring, forming a complex polycyclic structure. This composite molecular architecture is designed to enhance both the binding affinity (potency) and metabolic stability of the APJ receptor agonists
2Quantity of substance
If peptide agonists like apelin-13 are used, then high in vitro affinity is achieved, but the compounds have brief plasma half-life and transient circulating levels
Solution Approach 1:
The patent applies mechanics substitution by replacing the peptide-based ligand system with a small molecule chemical system. Instead of using peptide agonists like apelin-13 that interact with the APJ receptor, the invention uses synthetically accessible small molecules with fused ring structures. This substitution transitions from a biological polymer system to a small molecule system, which typically exhibits improved metabolic stability and longer plasma half-life while maintaining or enhancing binding affinity
Solution Approach 2:
The patent addresses the short-lived nature of peptide agonists by developing small molecule alternatives that are more stable in circulation. The fused ring small molecule structures are designed to resist enzymatic degradation that rapidly breaks down peptides, thereby extending the duration of action and maintaining therapeutic levels for longer periods
Data Source
AI summary
Compounds of Formula I, pharmaceutically acceptable salts thereof, tautomers thereof, pharmaceutically acceptable salts of the tautomers, or mixtures thereof are agonists of the APJ Receptor and may have use in treating cardiovascular and other conditions. Compounds of Formula (I) have the following structure: where the definitions of the variables are provided herein.