Newer ACE inhibitors. A look at the future

Area of Science:

• Pharmacology and Medicinal Chemistry
• Cardiovascular Drug Development

Background:

• Approximately 78 novel angiotensin converting enzyme (ACE) inhibitors are under investigation.
• At least 11-12 new ACE inhibitors are anticipated for clinical availability.
• Newer ACE inhibitors are chemically classified into sulfhydryl-, carboxyl-, and phosphoryl-containing groups based on their zinc ion ligand.

Purpose of the Study:

• To review and classify newly developed ACE inhibitors.
• To compare the pharmacokinetic properties and clinical potential of novel ACE inhibitors.
• To elucidate the chemical classes and in vivo conversion of prodrug ACE inhibitors.

Main Methods:

• Classification of novel ACE inhibitors based on chemical structure (sulfhydryl-, carboxyl-, phosphoryl-containing).
• Comparison of pharmacokinetic profiles, including onset, duration of action, peak time, half-life, and elimination routes.
• Analysis of prodrug conversion to active diacids and non-prodrug inhibitors.

Main Results:

• Sulfhydryl-containing inhibitors (e.g., alacepril, moveltipril) are prodrugs converted to captopril, showing longer action than captopril.
• Carboxyl-containing inhibitors are prodrugs excreted renally, with varied pharmacokinetic profiles (e.g., benazepril, ramipril, spirapril).
• Phosphoryl-containing inhibitor (fosinopril) is a prodrug with late peak time and dual liver/kidney elimination; SQ 29852 is a non-prodrug with prolonged effect.

Conclusions:

• Despite pharmacokinetic differences, newer ACE inhibitors are expected to provide similar ACE inhibition when dosages are adjusted.
• Variations in timing and duration of ACE inhibition depend on individual drug pharmacokinetic properties.
• The role of prostaglandin synthesis stimulation in antihypertensive action is considered minor and not specific to this drug class.