Targeting ACE and ECE with dual acting inhibitors

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Cardiovascular Research

Background:

• Angiotensin-converting enzyme (ACE) inhibitors are crucial in managing cardiovascular diseases.
• Dual inhibitors targeting ACE and other enzymes like endothelin-converting enzyme (ECE) offer potential therapeutic advantages.
• Previous research identified SA6817 analogues and GSK phosphonic acid derivatives with ACE inhibitory properties.

Purpose of the Study:

• To synthesize and evaluate novel urea analogues and a phosphonic acid derivative for dual ACE and ECE inhibitory activity.
• To explore the structure-activity relationships of these compounds against ACE and ECE.
• To identify potential candidates for further development as cardiovascular therapeutics.

Main Methods:

• Synthesis of a series of urea analogues based on SA6817 and a GSK phosphonic acid.
• In vitro enzymatic assays to determine inhibitory activity against ACE and ECE.
• Assessment of neutral endopeptidase (NEP) inhibition for selected compounds.

Main Results:

• Several synthesized urea analogues demonstrated excellent inhibition of ACE and NEP.
• One analogue showed significant ACE and NEP inhibition alongside modest ECE inhibition.
• The phosphonic acid derivative's dual activity profile was also evaluated.

Conclusions:

• The developed urea analogues show promise as potent dual ACE/NEP inhibitors.
• Further structural modifications may be necessary to enhance ECE inhibitory activity.
• These compounds represent a starting point for developing novel cardiovascular agents.