ACE = Angiotensin I Converting Enzyme

10 ACE inhibitors available in US: benazepril, captopril, enalapril, fosinopril,

lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril.
ACE inhibitors were the 4th most prescribed drug class in the U.S (159.8 million Rx
in 2008).
Lisinopril was the 2nd most prescribed drug in the US (75.5 million Rx in 2008).

Endogenously generated peptides are involved in the physiology and pathology of all major organ
systems and play important roles in many processes. These include neurotransmission, immune
function, cell proliferation, pain/analgesia, fluid balance in the kidney, endocrine functions, reproduction,
contraction/relaxation of all types of smooth muscle, regulation of the cardiovascular system,
satiety/obesity, etc.

1. TO MIMIC THE ACTION OF A PEPTIDE:

A. Administer the Peptide (See next page for advantages/disadvantages). Non-peptide agonists can be effective drugs,
however rational design of these drugs is generally not possible. Requires random/large scale screening approach.
B. Block the Degradation by Peptidase(s) - This is a good strategy because the level of the peptide can be specifically
increased at its normal site(s) of action and peptidase inhibitors can be synthesized with good stability and bioavailability.
Disadvantages include: 1) Blocking one peptidase may interfere with the metabolism of more than one peptide; 2) Inhibition of
more than one peptidase may be needed to block the degradation of a peptide 3) Enhancing general levels of a peptide with
multiple actions may produce side-effects.

2. TO BLOCK THE ACTION OF A PEPTIDE:

A. Use a Receptor Antagonist This is an excellent approach because the specific actions of a peptide mediated by a single
receptor type can be blocked, leading to the potential for few unwanted side effects. However, many peptide receptor
antagonists are themselves peptides and suffer from the disadvantages listed above. Development of non-peptide
antagonists may with good bioavailability and stability is possible, but is still not a straightforward process.

B. Block the Synthesis/Processing of the Peptide This is also an excellent approach and one exemplified by the
development of Angiotensin Converting Enzyme (ACE) inhibitors. In this approach, all the actions of the peptide can be
blocked and enzyme inhibitors can be synthesized with high affinity, specificity and bioavailability. However, disadvantages
include the following: 1) Cannot block a specific action of a peptide if it acts on more than one receptor. 2) Intermediate
forms of a peptide that build up when processing is blocked may have their own biological activity. 3)Processing enzymes
may process other peptide hormones. (ACE inhibitors do not suffer this disadvantage as the Renin-Angiotensin system
specifically processes and generates only angiotensin and not other peptides).

Top Left: Schematic diagram of the structure of human ACE. The majority of the ACE
molecule projects into the extracellular space and is boud to the plasma membrane via a
C-terminal transmembrane spanning helix, followed by a short 30 residue cytoplasmic
tail. The two homologous active site domains are denoted by the HEMGH sequence
which contains two zinc-binding histidine residues and the catalytic glutamic acid. The
distribution of carbohydrate is shown for all 17 potential Asn-linked glycosylation sites.
The extent of actual glycosylation varies from tissue to tissue and may not involve all
potential sites.
Top Middle: Superposition of the crystal structures of the N-domain (blue) and Cdomain (pink) showing the similarity of their primarily alpha-helical structures. Active site
zinc ion is shown in green.
Top Right: Space filling model of the C-domain of ACE showing the deep central groove
containing the active site and bound inhibitor lisinopril (yellow).
Bottom: Model of two possible orientations of the N- and C-domain in the ACE
holoenzyme.

A common misconception is that peptidases are peptide-specific, perpetuated by the

names given to some of the enzymes (e.g., Angiotensin I Converting Enzyme,
Enkephalinase, etc.). Peptidases recognize amino acids around the peptide-bond
being hydrolyzed and therefore can potentially cleave many different peptides.

Clinically used ACE inhibitors:

-In 1974, Cushman and Ondetti at Bristol-Meyers Squibb used a model based on the structure of
carboxypeptidase A and a snake venom peptide that inhibited ACE to synthesize captopril, which
contained a free SH group to bind the active site zinc. This was the first clinically used ACE
inhibitor. When the X-ray crystal structure of ACE was finally determined in 2003, it turned out to
have no homology to carboxypeptidase A.
-Because the -SH group can cause rash and taste disturbances at higher doses, second
generation ACE inhibitor enalaprilat used a -COOH group instead of SH to bind zinc. Most ACE
inhibitors use a free COOH group to bind zinc, except fosinopril,which uses phosphinic acid.
However, the free COOH or phosphinic acid group causes poor absorption, so they are
synthesized the prodrug esters which is absorbed well and converted by esterases to the active
drug. Only Lisinopril and Captopril are active compounds that do not require conversion.

Angiotensin Converting Enzyme (ACE) plays a central role in the control of peptide hormones that
regulate blood pressure. Thus, ACE inhibitors are effective antihypertensive agents.
Inhibitors of other steps in the pathway are also effective antihypertensives. These include Renin
inhibitors (Aliskiren, brand name Tekturna) and angiotensin receptor antagonists (the sartans
e.g., Losartan).

An additional mechanism by which ACE inhibitors can work involves the angiotensin metabolite,
Angiotensin 1-7 (1 residue shorter than angiotensin II). This metabolite can be generated directly
from angiotensin I by endopeptidases such as neutral endopeptidase, prolylendopeptidase and
thimet oligopeptidase.
Angiotensin 1-7, acting through its receptor (also called the Mas receptor), has effects opposite to
those of angiotensin II and thereby is a negative regulator of the renin-angiotensin system.
ACE inhibitors promote angiotensin 1-7 generation via 2 mechanisms: 1) increasing angiotensin
1 levels by inhibiting conversion to angiotensin II increases substrate concentration and thus
conversion by endopeptidases. 2) by blocking ACE metabolism of angiotensin 1-7 into the inactive
metabolite angiotensin 1-5.

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From Hypertension Primer, 4th Edition, edited by JL. Izzo, Jr., DA. Sica, HR. Black
Publisher: Lippincott Williams & Wilkins; (November 1, 2007)

11

From Hypertension Primer, 4th Edition, edited by JL. Izzo, Jr., DA. Sica, HR. Black
Publisher: Lippincott Williams & Wilkins; (November 1, 2007)

12

13

Side Effects/Contraindications
Common
Dry Cough

5 20% of patients
p
Not dose-related; occurs within 1 wk. 6 mo.
Women > men
May Require cessation of therapy

Fetopathic Potential
Not teratogenic in 1st trimester
Developmental
De elopmental defects in 2nd or 3rd trimester

Rare
Angioneurotic Edema (or Angioedema)

~0.1 - 0.5% of patients

Not dose-related; occurs within 1st week
Severe swelling of mouth,
mouth tongue,
tongue lips,
lips airway
may be life-threatening

Side Effects/Contraindications
Rare
Hypotension
First dose effect in p
patients with elevated PRA,, salt depletion,
p
, CHF

Hyperkalemia
In patients with renal insufficiency, diabetic nephropathy

Acute
A t Renal
R
lF
Failure
il
Patients with renal stenosis, heart failure, volume depleted

Skin Rash

Extremely Rare (reversible)

Alteration/loss of taste
Neutropenia
Glycosuria
Hepatotoxicity

Drug Interactions
Antacids
May reduce bioavailability of ACE inhibitors

Capsaicin
May worsen ACE inhibitor-induced cough

NSAIDs
May reduce antihypertensive response to ACE inhibitors

K+-sparing
sparing Diuretics or K+ supplements
May exacerbate ACE inhibitor-induced hyperkalemia

Novel and Unexpected Functions of ACE

and ACE inhibitors
ACE inhibitors potentiate B2 bradykinin receptor signaling by inducing crosstalk between ACE and
B2 receptor. (Erds EG, Deddish PA, and Marcic BM. Potentiation of Bradykinin Actions by ACE Inhibitors. Trends Endocrinol Metab 10:
223-229, 1999.)

ACE inhibitors bind directly to B1 kinin receptors and induce high output nitric oxide production in
endothelial cells. (Ignjatovic T, Tan F, Brovkovych V, Skidgel RA, and Erds EG. Novel mode of action of angiotensin I converting enzyme
inhibitors: direct activation of bradykinin B1 receptor. J Biol Chem 277: 16847-16852, 2002)

ACE itself is a signaling molecule that can be phosphorylated, activating JNK kinase and gene
transcription in response to ACE inhibitors. (Kohlstedt, K., Brandes, R. P., Muller-Esterl, W., Busse, R. and Fleming, I.
Angiotensin-converting enzyme is involved in outside-in signaling in endothelial cells. Circ. Res. 94, 60-7, 2004).

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Other antihypertensive drugs that interfere with the Renin-Angiotensin System

Ki i
Kininogen

A i t
Angiotensinogen
i

Kallikrein

Renin

Bradykinin

Angiotensin I
(Inactive)

B2
Receptor

ACE
Angiotensin II
AT1
Receptor

Angiotensin Bradykinin(1-7)
Receptor
(Inactive)
Antagonists
(the sartans
sartans ,
e.g. Losartan)

Vasoconstriction
Aldosterone release
Na+ Retention

Blood
Pressure

Vasodilation
Na+ Excretion

Other antihypertensive drugs that interfere with the Renin-Angiotensin System

Ki i
Kininogen

A i t
Angiotensinogen
i
Renin
Inhibitor
Aliskiren

Renin

Kallikrein

Bradykinin

Angiotensin I
(Inactive)

B2
Receptor

ACE
Angiotensin II
Bradykinin(1-7)
(Inactive)

AT1
Receptor
Vasoconstriction
Aldosterone release
Na+ Retention

Blood
Pressure

Vasodilation
Na+ Excretion