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 I Angiotensin II Decapeptide Octapeptide Aspartic acid Arginine ACE Aspartic acid Arginine Valine Tyrosine Valine Tyrosine Isoleucine Histidine Isoleucine Histidine Proline Phenyl alanine Proline Phenyl alanine - Histidine - Leucine

Functions of ACE
Angiotensinogen

Angiotensin I
+

Bradykinin ACE
+

Prostaglandin Release

Angiotensin II (Vasoconstrictor) Potent effect

Inactive Bradykinin

Vasodilatation

Net result is vasoconstriction

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

I. Sulfhydryl-containing ACE inhibitors

Captopril

Captopril was the first ACE inhibitor developed

Not a prodrug

II. Dicarboxylate-containing ACE inhibitors

This is the largest group, including: Enalapril

Ramipril
Quinapril Perindopril Lisinopril Esters are act as prodrug
Enalapril

Lisinopril (orally active without being prodrug)

III. Phosphonate-containing ACE inhibitors

Fosinopril, the only member

Active Sites in ACE

To which angiotensin I or drug binds
Zinc ion (Zn+2) Charged arginine unit (=NH2+) Hydrophobic pocket
Arginine

General structure of ACE inhibitors

COOH

Phosphonic acid Sulfhydryl Carboxylic acid

Alanine Lysine