Angiotensin Converting Enzyme Inhibitors & angiotensin

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Transcript of Angiotensin Converting Enzyme Inhibitors & angiotensin

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.
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.
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
Natriuretic; ↓ RVR;
1 2 3 7 8 9 10
NH2-Asp-Arg-Val…Pro-Phe-COOH
NH2-Arg-Val…Pro-Phe-COOH 2 3 7 8
NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH
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
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
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:
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
6
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.
7
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.
8
9
The search for ACE inhibitors that lacked
the sulfhydryl group also led to the
investigation of phosphorous-containing
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
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.
CH C
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.
12
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.