ACE Inhibitors

PHRM 304

Schematic drawing shows the structure of ACE. There is a catalytic site on each extracellular lobe, each of which binds a zinc (Zn2+) atom.

ACE

• Angiotensin Converting Enzyme (ACE) catalyzes hydrolysis of dipeptide fragment

• Convert of angiotensin I (decapeptide) to angiotensin II (octapeptide)

• ACE inhibitors are competitive inhibitor

Competitive Inhibition

Non-competitive Inhibition

Angiotensins

• Angiotensin IDecapeptide

Aspartic acid – Arginine – Valine – Tyrosine – Isoleucine – Histidine – Proline – Phenyl alanine - Histidine - Leucine

• Angiotensin IIOctapeptide

Aspartic acid – Arginine – Valine – Tyrosine – Isoleucine – Histidine – Proline – Phenyl alanine

ACE

Angiotensinogen

Angiotensin I

Angiotensin II(Vasoconstrictor)

Potent effect

Bradykinin

Inactive Bradykinin

ACE

ProstaglandinRelease

Vasodilatation

+ +

Net result is vasoconstriction

Functions of ACE

Functions of ACE

ACE Side effects

• Dry cough in elderly (10-15% patient)• Common among women• Increase in bradykinin also increase

prostaglandin release which causes dry cough

ACE inhibitors

• 11 approved inhibitors are available• Based on chemical composition classified into

three groups

Captopril

I. Sulfhydryl-containing ACE inhibitors

Captopril was the first ACE inhibitor developed

Not a prodrug

This is the largest group, including:

Enalapril

Ramipril

Quinapril

Perindopril

Lisinopril

II. Dicarboxylate-containing ACE inhibitors

Enalapril

Esters are act as prodrug

Lisinopril (orally active without being prodrug)

Fosinopril, the only member

III. Phosphonate-containing ACE inhibitors

Active Sites in ACE

• To which angiotensin I or drug binds– Zinc ion (Zn+2)– Charged arginine unit (=NH2

+)– Hydrophobic pocket

Arginine

Sulfhydryl Carboxylic acid

Phosphonic acid

General structure of ACE inhibitors

COOH

Alanine

Lysine