1

Angiotensin-Converting Enzyme

Inhibitors & angiotensin receptor

blockers (1)

Dr.Majdi Bkhaitan

www.uqu.edu.sa/mmbakhaitan

mmbakhaitan@uqu.edu.sa

Clinical Significance

“The treatment of hypertension and congestive heart failure (CHF) has improved

significantly with the introduction of angiotensin-converting enzyme (ACE) inhibitors,

angiotensin receptor blockers, and calcium channel blockers. The SARs and structural

modifications of these agents have produced major therapeutic advances. These drugs

have become cornerstones of therapy today.

For example, more than 25 years ago, captopril was the first ACE inhibitor to be

developed. Subsequent molecular modifications led to the development of newer agents,

such as lisinopril. Al though lisinopril exerts comparable ACE inhibition, it possesses a

superior pharmacokinetic profile. Instead of having to administer captopril three times

daily, lisinopril can be administered once daily

Medication compliance is notoriously poor in cardiovascular patients. Administering an

ACE inhibitor such as lisinopril once daily results in greatly enhanced medication

compliance. The therapeutic outcomes of patients with hypertension and CHF have

improved immensely as a result. Similar molecular enhancements have been made with

angiotensin receptor blockers and calcium channel blockers.

The application of basic science in modifying the chemical structure of these agents has

ultimately resulted in patients living longer and suffering fewer cardiovascular events,

such as myocardial infarction or worsening CHF. Importantly, their day-to-day quality

of life is preserved as well”

Thomas L. Rihn, Pharm.D.

University Pharmacotherapy Associates

Associate Professor of Clinical Pharmacy

Duquesne University/ School of Pharmacy

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Antihypertensive Therapy (Foy’s, sixth edition)

The Renin-Angiotensin Pathway

The renin-angiotensin system is a complex, highly regulated pathway that is integral in

the regulation of blood volume, electrolyte balance, and arterial blood pressure. It

consists of two main enzymes, renin and angiotensin-converting enzyme (ACE), the

primary purpose of which is to release angiotensin II from its endogenous precursor,

angiotensinogen. Angiotensin II is a potent vasoconstrictor that affects peripheral

resistance, renal function, and cardiovascular structure. Angiotensinogen is an α2-

globulin with a molecular weight of 58,000 to 61,000 daltons. It contains 452 amino

acids, is abundant in the plasma, and is continually synthesized and secreted by the liver.

A number of hormones, including glucocorticoids, thyroid hormone, and angiotensin II,

stimulate its synthesis. The most important portion of this compound is the N-terminus,

specifically the Leu10-Val11 bond. This bond is cleaved by renin and produces the

decapeptide angiotensin I. The Phe8-His9 peptide bond of angiotensin I is then cleaved

by ACE to produce the octapeptide angiotensin II. Aminopeptidase can further convert

angiotensin II to the active heptapeptide angiotensin III by removing the N-terminal

arginine residue. Further actions of carboxypeptidases, aminopeptidases, and

endopeptidases result in the formation of inactive peptide fragments. An additional

compound can be formed by the action of a rolylendopeptidase on angiotensin I.

Cleavage of the Pro7-Phe8 bond of angiotensin I produces a heptapeptide known as

angiotensin 1-7.

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Actions and Properties of Renin-Angiotensin Pathway Components

Angiotensin II is the dominant peptide produced by the renin-angiotensin pathway. It is a

potent vasoconstrictor that increases total peripheral resistance through a variety of

mechanisms: direct vasoconstriction, enhancement of both catecholamine release and

neurotransmission within the peripheral nervous system, and increased sympathetic

discharge. The result of all these actions is a rapid pressor response. Additionally,

angiotensin II causes a slow pressor response, resulting in a long term stabilization of

arterial blood pressure. This long-term effect is accomplished by the regulation of renal

function. Angiotensin II directly increases sodium reabsorption in the proximal tubule. It

also alters renal hemodynamics and causes the release of aldosterone from the adrenal

cortex. Finally, angiotensin II causes the hypertrophy and remodeling of both vascular

and cardiac cells through a variety of hemodynamic and non-hemodynamic effects

Angiotensinogen

Angiotensin I

Angiotensin II

Angiotensin III

Renin

ACE

Aminopeptidase

Non-ACE

(eg. Chymase

in heart)

Endopeptidase

Angiotensin 1-7Releases ADH; ↑ PG;

Natriuretic; ↓ RVR;

↓ BP (brain stem inj.)

? Role in effects of ACEI

1 2 3 7 8 9 10

NH2-Asp-Arg-Val…Pro-Phe-COOH

1 2 3 7 8 9 10

NH2-Asp-Arg-Val…Pro-Phe-COOH1 2 3 7 8

NH2-Arg-Val…Pro-Phe-COOH2 3 7 8

NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH

+

1. ↓ Renal Perfusion

Pressure

2. ↓ Na at Macula

Densa cells

3. ↑ Sympathetic

nerve activity (ß-1)

±PG

The Renin-Angiotensin System

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Angiotensin II versus Bradykinin

Bradykinin is a nonapeptide that acts locally to produce pain, cause vasodilation, increase

vascular permeability, stimulate prostaglandin synthesis, and cause bronchoconstriction.

The degradation of bradykinin to inactive peptides occurs through the actions of ACE.

Thus, ACE not only produces a potent vaso-constrictor but also inactivates a potent

vasodilator

Role of the Renin-Angiotensin

Pathway in Cardiovascular

Disorders Because the renin-angiotensin pathway is

central to the maintenance of blood

volume, arterial blood pressure, and

electrolyte balance, abnormalities in this

pathway (e.g., excessive release of renin

and overproduction of angiotensin II) can

contribute to a variety of cardiovascular

disorders. Specifically, over-activity of this

pathway can result in hypertension or heart

failure via the mechanisms previously

described. Abnormally high levels of

angiotensin II can contribute to

hypertension through both rapid and slow

pressor responses. Additionally, high

levels of angiotensin II can cause cellular

hypertrophy and increase both afterload

and wall tension. All of these events can

cause or exacerbate heart failure. Model showing cleavage of the histidine-phenylalanine residue of angiotensin I by ACE to form the octapeptide angiotensin II and the dipeptide residue of histidine and leucine

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Role of Drug Therapy Affecting the Renin-Angiotensin Pathway

Because angiotensin II produces the majority of the effects attributed to the renin-

angiotensin pathway, compounds that can block either the synthesis of angiotensin II or

the binding of angiotensin II to its receptor should attenuate the actions of this pathway.

Indeed, enzyme inhibitors of both renin and ACE, as well as receptor antagonists of

angiotensin II, have all been shown to produce beneficial effects in decreasing the actions

of angiotensin II.

Angiotensin-Converting Enzyme Inhibitors Currently, there are 11 ACE inhibitors approved for therapeutic use in the United States.

These compounds can be sub-classified into three groups based on their chemical

composition:

Sulfhydryl-containing inhibitors (exemplified by captopril).

Dicarboxylate-containing inhibitors (exemplified by enalapril).

Phosphonate-containing inhibitors (exemplified by fosinopril).

Captopril and fosinopril are the lone representatives of their respective chemical sub-

classifications, whereas the majority of the inhibitors contain the dicarboxylate

functionality. All of these compounds effectively block the conversion of angiotensin I to

angiotensin II and have similar therapeutic and physiological effects. The compounds

differ primarily in their potency and pharmacokinetic profiles. Additionally, the

sulfhydryl group in captopril is responsible for certain effects not seen with the other

agents.

Sulfhydryl-containing inhibitors

The development of captopril and other orally active ACE inhibitors began with the

observation that D-2-benzylsuccinic acid was an extremely potent inhibitor of

carboxypeptidase. The binding of this compound to carboxypeptidase A (Fig. 28.6A) is

very similar to that seen for substrates with the exception that the zinc ion binds to a

carboxylate group instead of the labile peptide bond.

Applying this concept to the hypothetical model of ACE described above resulted in the

synthesis and evaluation of a series of succinic acid derivatives (Fig. 28.6B). Because

proline was present as the C-terminal amino acid in potent inhibitory snake venom

peptides, it was included in the structure of newly designed inhibitors. The first inhibitor

to be synthesized

and tested was

succinyl-L-proline

(Fig. 28.7). This

compound proved

to be somewhat

disappointing. Al

though it provided

reasonable

specificity for

ACE, it was only

approximately 1/500 as potent as snake venom.

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One of the most important alterations to succinyl-L-proline was the replacement of the

succinyl carboxylate with other groups having enhanced affinity for the zinc atom bound

to ACE. Replacement of this carboxylate with a sulfhydryl group produced 3-

mercaptopropanoyl-L-proline. This compound has an IC50 value of 200 nM and is

greater than 1000-fold more potent than succinyl-L-proline (Fig. 28.7).

Additionally, it is 10- to 20-fold more potent than snake venom in inhibiting contractile

and vasopressor responses to angiotensin I. Addition of a D-2- methyl group further

enhanced activity. The resulting compound, captopril (Fig. 28.7), is a competitive

inhibitor of ACE with a Ki value of 1.7 nM and was the first ACE inhibitor to be

marketed.

The sulfhydryl group of captopril proved to be responsible not only for the excellent

inhibitory activity of the compound but also for the two most common side effects, skin

rashes and taste disturbances (e.g., metallic taste and loss of taste). These side effects

usually subsided on dosage reduction or discontinuation of captopril. They were

attributed to the presence of the sulfhydryl group, because similar effects had been

observed with penicillamine, a sulfhydryl containing agent used to treat Wilson's disease

and rheumatoid arthritis.

Dicarboxylate-containing inhibitors

Researchers at Merck sought to develop compounds that lacked the sulfhydryl group of

captopril yet maintained some ability to chelate zinc. Compounds

having the general structure shown here were designed to meet this

objective. These compounds are tripeptide substrate analogues in

which the C-terminal (A) and penultimate (B) amino acids are

retained but the third amino acid is isosterically replaced by a

substituted N-carboxymethyl group. The use of a methyl group at R3

(i .e., B = Ala) and a phenylethyl group at R4 resulted in enalaprilat

(Fig. 28.8). In comparing the activity of captopril and enalaprilat, it

was found that enalaprilat, with a Ki of 0.2 nM, was approximately 10-fold more potent

than captopril. Despite excellent activity, enalaprilat has very poor oral bioavailability.

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Esterification of enalaprilat produced enalapril, a compound with superior oral

bioavailability. The combination of structural features in enalaprilat, especially the two

carboxylate groups and the secondary amine, are responsible for its overall low

lipophilicity and poor oral bioavailability.

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Phosphonate-containing Inhibitors: the Development of Fosinopril

The search for ACE inhibitors that lacked

the sulfhydryl group also led to the

investigation of phosphorous-containing

compounds. The phosphinic acid shown

in Figure 28.11 is capable of binding to

ACE in a manner similar to enalapril. The

interaction of the zinc atom with the

phosphinic acid is similar to that seen

with sulfhydryl and carboxylate groups.

Additionally, this compound is capable of

forming the ionic, hydrogen, and

hydrophobic bonds similar to those seen

with enalapril and other dicarboxylate

analogues. A feature unique to this

compound is the ability of the phosphinic

acid to more truly mimic the ionized,

tetrahedral intermediate of peptide

hydrolysis.

Structure–Activity Relationships of

ACEI’s

The structural characteristics for ACE

inhibitory activity are given below.

Angiotensin-converting enzyme is a

stereoselective drug target. Because currently approved ACE inhibitors act as either di- or

tripeptide substrate analogues, they must contain a stereochemistry that is consistent with the

L-amino acids present in the natural substrates The S,S,S-configuration seen in enalapril and

other dicarboxylate inhibitors meets the above-stated criteria and provides for optimum

enzyme inhibition.

1. The N-ring must contain a carboxylic acid to mimic the C-terminal carboxylate of ACE

substrates.

2. Large hydrophobic heterocyclic ring (i.e. N-ring) increase potency and alter

pharmacokinetic parameters.

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3. The Zn binding groups can be sulfahydryl, carboxylic acid, or phosphonic acid.

4. The sulfahydryl group shows superior binding to Zn (the side chain mimicking Phe in

carboxylate and phosphonic acid compounds compensates for the lack of a sulfahydryl

group.)

5. Sulfahydryl containing compounds produce high incidence of skin rash and taste

disturbances.

6. Sulfahydryl containing compounds can form dimers that may shorten duration of action.

7. Esterification of the carboxylic acid or phosphonic acid drugs improves oral

bioavailability.

8. X is usually a methyl to mimic the side chain of alanine.

9. Optimum activity occurs when stereochemistry of inhibitors is consistent with L-amino

acid stereochemistry present in normal substrates.

Therapeutic Applications

The ACE inhibitors have been approved for the treatment of hypertension, heart failure, left

ventricular dysfunction (either post–myocardial infarction [MI] or asymptomatic), improved

survival post-MI, diabetic nephropathy, and reduction of the risk of MI, stroke, and death from

cardiovascular causes. Although all ACE inhibitors possess the same physiological actions and,

thus, should produce similar therapeutic effects, the approved indications differ among the

currently available agents.

Angiotensin II Receptor Blockers Efforts to develop angiotensin II receptor

antagonists began in the early 1970s and

focused on peptide-based analogues of the

natural agonist. The prototypical compound

that resulted from these studies was

Saralasin. Saralasin as well as other peptide

analogues demonstrated the ability to

reduce blood pressure; however, these

compounds lacked oral bioavailability and

expressed unwanted partial agonist activity.

More recent efforts have used peptide

mimetics to circumvent these inherent problems

with peptide-based antagonists. The culmination of

these efforts was the 1995 approval of losartan, a

nonpeptide angiotensin II receptor blocker (ARB).

The development of losartan can be traced back to

two 1982 patent publications, which described the

antihypertensive effects of a series of imidazole-5-

acetic acid analogues and were later found to block the angiotensin II receptor specifically.

CHC

H2C

OH

O

N

C

O

CH

C

CH2

O

N

HN

CH

CCH

OH3C

H2C

CH3

NH

HN

CH

C

CH2

O

OH

CH

C

CH

O

H3C CH3

CH

CH2C

OCH2

CH2

HN

C

NH2

HN

NH2

CH

C

H2C

O

C

OH

O

NH

NH

HN

HN

Angiotensin II

NN

Cl

N

HN N

N

HO

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Products

Candesartan Cilexetil, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan, Valsartan.

Mechanism of Action

SAR of Angiotensin II Antagonists

The “acidic group” is thought to mimic either the Tyr4 phenol or the Asp1 carboxylate of

angiotensin II. Groups capable of such a role include the carboxylic acid (A), a phenyl

tetrazole (B), or a phenyl carboxylate (C).

In the biphenyl series, the tetrazole and carboxylate groups must be in the ortho

position for optimal activity (the tetrazole group is superior in terms of metabolic

stability, lipophilicity, and oral bioavailability).

The n-butyl group of the model compound provides hydrophobic binding and, most

likely, mimics the side chain of Ile5 of angiotensin II. As seen with candesartan,

telmisartan, and olmesartan, this n-butyl group can be replaced with either an ethyl

ether or an n-propyl group.

The imidazole ring or an isosteric equivalent is required to mimic the His6 side chain 4.

of angiotensin II.

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Substitution can vary at the “R” position. A variety of R groups, including a carboxylic

acid, a hydroxymethyl group, a ketone, or a benzimidazole ring, are present in currently

available ARBs and are thought to interact with the AT1 receptor through either ionic,

ion–dipole, or dipole–dipole bonds.

1) Foy’s Principles of Medicinal Chemistry, chapter 28, sixth edition.