Discovery and development of ACE inhibitors

File:ACE and inhibitor.jpg

Discovery and Development of ACE Inhibitors

The discovery and development of Angiotensin-Converting Enzyme (ACE) inhibitors represent a significant advancement in the field of cardiovascular medicine. These drugs are primarily used to treat hypertension and congestive heart failure, and they work by inhibiting the activity of the enzyme responsible for converting angiotensin I to angiotensin II, a potent vasoconstrictor.

Historical Background

The journey to the discovery of ACE inhibitors began with the study of the renin-angiotensin system (RAS), a hormone system that regulates blood pressure and fluid balance. In the 1950s, researchers identified angiotensin II as a key player in blood pressure regulation. The search for inhibitors of this system led to the discovery of ACE inhibitors.

Discovery of ACE

Angiotensin-Converting Enzyme (ACE) was first identified in the 1950s. It was found to be a dipeptidyl carboxypeptidase that converts the inactive decapeptide angiotensin I into the active octapeptide angiotensin II. This conversion is crucial for the regulation of blood pressure and electrolyte balance.

Development of ACE Inhibitors

The development of ACE inhibitors was inspired by the study of snake venom. In the 1960s, researchers discovered that the venom of the Brazilian pit viper, *Bothrops jararaca*, contained peptides that could inhibit ACE. This led to the synthesis of the first ACE inhibitor, teprotide, which was effective but not suitable for oral administration.

Captopril

The first orally active ACE inhibitor, captopril, was developed in the late 1970s by researchers at Squibb (now Bristol-Myers Squibb). Captopril was designed based on the structure of teprotide and was approved by the FDA in 1981. It was a breakthrough in the treatment of hypertension and heart failure.

Enalapril and Other ACE Inhibitors

Following the success of captopril, other ACE inhibitors were developed, including enalapril, lisinopril, and ramipril. Enalapril, a prodrug that is converted to the active form enalaprilat in the body, offered improved pharmacokinetic properties and was approved in 1985.

Mechanism of Action

ACE inhibitors work by blocking the conversion of angiotensin I to angiotensin II. This leads to vasodilation, reduced secretion of aldosterone, and decreased blood pressure. By reducing the effects of angiotensin II, ACE inhibitors also decrease the workload on the heart, making them effective in treating heart failure.

Clinical Applications

ACE inhibitors are used to treat a variety of cardiovascular conditions, including:

• Hypertension
• Congestive heart failure
• Myocardial infarction
• Diabetic nephropathy

Side Effects and Contraindications

Common side effects of ACE inhibitors include cough, hyperkalemia, and hypotension. They are contraindicated in patients with a history of angioedema related to previous ACE inhibitor therapy and in pregnant women due to the risk of fetal toxicity.

Also see

• Renin-angiotensin system
• Hypertension
• Heart failure
• Angiotensin II receptor blockers