Antihypertensive Drugs May 8, 2018opencourses.emu.edu.tr/pluginfile.php/35633/mod_forum...2018/05/08 · Altan Bilgin ve Prof. Dr. Cihat Şafak (2004) in Turkish 6) Farmasötik Kimya

PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM

ANTIHYPERTENSIVE DRUGS

Prof. Dr. Erçin ERCİYAS

May 8, 2018




This course notes have been prepared from the references listed below and thelecturer strongly suggests students to use them for providing deeper knowledge.

1) Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical

Chemistry, 12.Edition, Edited by John B. Beale Jr, John H. Block, (Lippincott

Williams & Wilkins, 2011).

2) Foye’s Principles of Medicinal Chemistry, 6th.Edition, Edited by Thomas L.

Lemke, David A. Williams, Victoria F. Roche, S. William Zito, (Lippincott

Williams & Wilkins, 2008).

3) http:// www.cvpharmacology.com (Author: Richard E. Klabunde)

4) http//www.drugsyn.org

5) Farmasötik Kimya, 2.Baskı, Redaksiyon : Prof. Dr. A. Altan Bilgin ve Prof. Dr.

Cihat Şafak (2004) in Turkish

6) Farmasötik Kimya Ders Notları, Ege Üniversitesi, Eczacılık Fakültesi,

Farmasötik Kimya Anabilim Dalı (in Turkish)

Prof. Dr. Erçin ERCİYAS, May 8, 20182


Hypertension can be defined as the increase of arterial blood pressure above the limits.

This chart reflects blood pressure categories defined by the American Heart Association.

from http://www.heart.org




There are two types of hypertension:

(a) Primary (Essential) Hypertension

(b) Secondary Hypertension

Most common type of hypertension

(90-95%)

Cause can not be identified

Cause can be identified

Such as renal hypertension (kidney

diseases), Pheochromocytoma




Diuretics

Centrally Acting Sympatholytics

Adrenergic Neuron Blockers

Adrenergic Receptor Blockers

bbbb-Adrenergic Receptor Blockers

aaaa1-Adrenergic Receptor Blockers

Direct Acting Vasodilators

Potassium Channel Agonists

Renin-Angiotensin System Inhibitors

Calcium Channel Blockers

Other Drugs

CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS

will be discussed in a separated section



BBBB-ADRENERGIC BLOCKERS

bbbb-Receptor Blockers reduce

(a) the heart rate,

(b) contractility

(c) arterial pressure

Activation of thebbbb1111 receptors in heart leads to an increase in rate and force of

contraction.

Depending upon these effects, these

drugs reduce the work and the oxygen

demand of heart and

improve the oxygen supply /demand

ratio.




bbbb-Receptor Blockers can be divided into two class depending on the receptor selectivity

(a) Nonselective bbbb-Receptor Blockers (bbbb1 and bbbb2 blocking effect) (First Generation)

Propranolol, timolol, nadolol, pindolol (some examples of this class)

(b)bbbb1-Selective Adrenergic Blockers (cardioselective bbbb1 blockers) (Second Generation)

Acebutolol, atenolol, metoprolol (some examples of this class)

Nonselective bbbb-Receptor Blockers with aaaa1 antagonistic activity (Third Generation)

labetalol,carvedilol




bbbb---- adrenergic receptor blockers are among the most widely used antihypertensive

drugs and also considered for the first line treatment for glaucoma.

Cardioselective bbbb1111---- adrenergic receptor blockers have a greater affinity for the bbbb1111 -

receptors in heart than for the bbbb2222-receptors in other tissue.

provides two important advantages(next slide please)




Cardioselective bbbb1111---- adrenergic receptor blockers have a greater affinity for the bbbb1111 -

receptors in heart than for the bbbb2222-receptors in other tissue.

provide two important advantagesbbbb1111-Blockers do not have blocking

effects on bbbb2222-receptors on bronchi

They can be used safely in patients with

bronchitis or bronchial astma

bbbb1 1 1 1 -Blockers do not have blocking

effects on vascular bbbb2222-receptors

mediating vasodilation




bbbb-Receptor Blockers are the derivatives of

(a) Aryloxypropanolamine (mostly) or

(b) Arylethanolamine



EXAMPLES OF BBBB-ADRENERGIC BLOCKERS

LABETALOL

It is arylethanolamine type bbbb-blockers.

Labetalol is competetive nonselective bbbb (bbbb1 and bbbb2) and aaaa1-receptor blocker.

Labetalol is clinically useful antihypertensive agent.




LABETALOL

Labetalol has two asymmetric centers (see the formula *).

Two asymmetric centers correspond to 4 stereoisomers (RR, SS / RS, SR).

Mixture of 4 stereoisomers is used in treating hypertension.

However, the different isomers possess different receptor blocking activities

(see nest slide) .

* *




LABETALOL

* * n: number of chiral centers

2n : number of stereoisomers

enantiomers

n: 1One chiral center 21 stereoisomers

REMINDER

2 enantiomers R

n: 2Two chiral center 22 stereoisomers 4 stereoisomers

R, S S, R R, R S, S

S

enantiomers

diastereoisomersProf. Dr. Erçin ERCİYAS, May 8, 201813



LABETALOL

* *

HO

C

HN

O NH2

OHCH3

R R only bbbb-blocker activity

S R aaaa1111-blocker activity

S S aaaa1111-blocker activity

R S

Possessing greater

therapeutic activity



PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-AUTUMN TERM


LABETALOL

2-hydroxybenzamide

ethyl

butyl

(salicylamide)


2-Hydroxy-5-[1-hydroxy-2-(4-phenylbutan-2-ylamino)ethyl]benzamide

15


EXAMPLES BBBB-ADRENERGIC BLOCKERS

CARVEDILOL

It is Aryloxypropanolamine type bbbb-blockers.

Carvedilol is competetive nonselective b b b b (bbbb1 and bbbb2) and aaaa1-receptor blocker.

It also has antioxidant and an antiproliferative effect on vascular smooth cells.

Therefore, it possesses neuroprotective effect and ability

to provide major cardiovascular organ protectionProf. Dr. Erçin ERCİYAS, May 8, 2018

1-(9H-carbazole-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol

1

carbazole

*4

31

16



CARVEDILOL

Carvedilol has one asymmetric center (see the formula *).

One asymmetric center leads to 2 stereoisomers (enantiomers).

Racemate is used in therapy.

However, the enantiomers possess diferent receptor blocking activities .

Both enantiomers (R,S) have aaaa1-receptor blocking effects

Only (S) enantiomer has bbbb-blocking effect



Diuretics










Other Drugs




aaaa1-ADRENERGIC RECEPTOR BLOCKERS

Nonselective aaaa-adrenergic receptor blockers are used in the treatment of catecholamine-

dependent hypertension.

These drugs , as non-specific –blocking agents, block both aaaa1 and aaaa2 adrenergic receptors.

Blocking presynaptic aaaa2 receptors leads to cardiac stimulatory effect and tachycardia.

Examples of nonselective aaaa----adrenergic receptor blockers are Tolazoline, Phentolamine and

Phenoxybenzamine.



NONSELECTIVE aaaa-ADRENERGIC RECEPTOR BLOCKERS

Talozoline

2-benzyl-4,5-dihydro-1H-imidazole

NH

N

N

OH

CH3

Phentolamine3-[(4,5-dihydro-1H-imidazol-2-yl) (p-tolyl) amino]phenol

used in persistent pulmonary hypertension of the newborn

(has been used to treat Raynaud Syndrome)




NH

N

N

OH

CH3

Phentolamine

used to prevent or control hypertensive episodes in patient

with pheochromocytoma

a neuroendocrine tumor of the medulla of adrenal glands





PhenoxybenzamineN-benzyl-N-(2-chloroethyl)-1-phenoxypropan-2-amine

irreversible nonselective aaaa-adrenergic blocker

2-chloroethyl group alkylates the receptor

binds the receptors covalently

Single dose of phenoxybenzamine may last 3 to 4 days.

It is used in pheochromocytoma.






Selective aaaa1-adrenergic receptor blockers are used in the treatment of hypertension.

produce antihpertensive effect by blocking the vasocontricting effect of aaaa1-adrenergic receptor

on smooth muscle.

These drugs do not have any effect on aaaa2-adrenergic receptors.

Examples of selective aaaa1111----adrenergic receptor blockers are Prazosin, Terazosin and Doxasozin.




PRAZOSİN

N

N

QuinazolineBenzo[d]pyrimidine

4

3

12

5

6

7

8

piperazine

12 3

4

Furan

1

2

34

5

2-Furoic acidfuran-2-carboxylic acid

4-Amino-2-[4-(2-furoyl)piperazin-1-yl]-6,7-dimethoxyquinazoline


İupac: [4-(4-Amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(furan-2-yl)methanone

24


SYNTHESIS OF PRAZOSİN


2-amino-4,5-dimethoxybenzoic acid

Sodium cyanate

(NaOCN)

SOCl2

Thionyl chloride




SYNTHESIS OF PRAZOSİN (continuing)

NH3

1-(2-furoyl)piperazine




PRAZOSİN

Prazosine is orally used as hydrochloride salt.

Plasma half life is 2 to 3 hours.

Side effects include dizziness, orthostatic hypotension (due to loss of reflex vasoconstriction

upon standing).

Amino group at 4th position of quinazoline ring

is very important for the aaaa1 receptor affinity




TERAZOSİN

DOXAZOSİN

2,3-dihydrobenzo[b][1,4]dioxine

(tetrahydrofuran)

Amino group at 4th position of quinazoline ring

is very important for the aaaa1 receptor affinity.


Saturated furan

[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(2,3-dihydro-1,4-benzodioxin-3-yl)methanone

[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(oxolan-2-yl)methanone

28


Diuretics










Other Drugs




Adrenergic Neuron Blockers are comprised of two different groups:

(a) Reserpine and Derivatives

(b) Guanidine Derivatives

ADRENERGİC NEURON BLOCKERS




RESERPINE

Reserpine is an alkaloid isolated from the roots of Rauwolfia Serpentina.

It affects the storage and release of norepinephrine. It depletes catecholamines and serotonine

from central and peripheral neurons by interfering with the uptake of these amines.

Reserpine is the first effective antihypertensive drug in western medicine.

It has largely been replaced by newer agents with fewer side effects.




RESERPINE

As indole derivatives, it is sensitive to decomposition by light and oxidation, especially in

solution.

Reserpine is used orally or parenterally for the treatment of hypertension.


32



Guanethidine prevents the release of norepinepherine from the postganglionic

neurons in response to sympathetic nerve stimulation and causes depletion of it in

adrenergic neurons.

İt is used orally for antihypertensive therapy.

2-[2-(azocan-1-yl)ethyl]guanidine


GUANETHIDINEOcane: Suffixes for fully saturatedeight membered ring without nitrogen

33


Diuretics










Other Drugs




CENTRALLY ACTING SYMPATHOLYTIC DRUGS

Centrally acting sympatholytic drugs are aaaa2-adrenergic receptor agonists.

These drugs cause a decrease in sympathetic outflow from the central nervous system.

Therefore, they decrease the peripheral vascular resistance, blood pressure and heart

rate and contractility.

Clonidine, aaaa-methyldopa, guanabenz and guanafacine are examples of this class.



CLONIDINECENTRALLY ACTING SYMPATHOLYTIC DRUGS

1H-Imidazole

NH

NHN

Cl

Cl

4 3

1

25

NH

NH

2,3-dihydro-1H-imidazole(4-imidazoline)


NH

NH

REMINDER

Imidazolidine

Indicated Hydrogen



CLONIDINECENTRALLY ACTING SYMPATHOLYTIC DRUGS

1H-Imidazole

2,6-dichloro-N-(2-imidazolin-2-yl)aniline

2-[(2,6-dichlorophenyl)amino]-2-imidazoline

NH

NHN

Cl

Cl

4 3

1

25

NH

NH



REMINDER

indicate the saturated positions

indicate double bond’s position



REMINDER

Tautomers are two forms of the same compound which differ by positions of a hydrogen atom and a pi bond. The

Equilibrium arrow is used to show the tautomer equlibrium.

For example ketones and enols are tautomers:

Tautomerization is the process of isomerization of one tautomer into another tautomer.

What is tautomerization ?

ketone enol

NH

NHN

Cl

Cl

NH

HN

N

Cl

Cl

Clonidine tautomers can be drawn as follows



NH2

ClCl NH4SCN

CH3I

SYNTHESIS OF CLONIDINE

(Ammonium thiocyanate)

2,6-dichlorophenylthiourea

2,6-dichlorophenyl-S-methylisothiourea

2,6-dichloroaniline

- HI



H2NCH2CH2NH2N

Cl

Cl

C

SCH3

NH

H-CH3SH

-NH3NH

NHN

Cl

Cl

SYNTHESIS OF CLONIDINE


CLONIDINE

N

CH2

CH2

N

H

H

H

H

+

2,6-dichlorophenyl-S-methylisothiourea



CLONIDINE


As a centrally acting drug, at physiological pH,

it exists to a significant extent in the nonionized form.

The nonionized form can pass the membranes and / or BBB

(Blood Brain Barrier).

NH

NHN

Cl

Cl

NH

HN

N

Cl

Cl

Guanidine



CLONIDINE



it exists to a significant extent in the nonionized form

How can we explain this dilemma ?

Guanidine (strong basic) (pKa=13.6)

ionized at physiological pHClonidine bears a guanidine moiety

NH

NHN

Cl

Cl



CLONIDINE

NH

HN

N

Cl

Cl



it exists to a significant extent in the nonionized form.

pKa of clonidine is much more lower than guanidine’s pKa.

Guanidine (strong basic) (pKa=13.6)

Clonidine(pKa= 8.0)

Because of the inductive and

resonanse effects of dichlorophenyl

ring

The basicity of clonidine is

decreased


43


GUANABENZ


GUANFACINE


2-[(E)-(2,6-dichlorophenyl)methylideneamino]guanidine

N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide

44


GUANABENZ


GUANFACINE

Guanidine

CLONIDINE

CLONIDINE GUANABENZGUANFACINE> >Elimination half-life is decreasing

20-25h 17h 3h




METHYLDOPA

HO

HO

CH2 C

NH2

H

COOH

L-DOPA

Dopa is the precursor of the catecholamines

[dopamine, norepinephrine (noradrenaline)

and epinephrine (adrenaline)].

Also used as antiparkinson drug.

*

*

Flying wedge projection of L-Methyldopa

L-Methyldopa has S configuration

?



An arbitrary convention according to which (+)-glyceraldehyde was named D-

glyceraldehyde (with the enantiomer L-glyceraldehyde and its racemate DL-

glyceraldehyde).

From IUPAC Gold Book

D / L CONVENTION IN STEREOCHEMISTRY

REMINDER

D-glyceraldehyde L-glyceraldehyde

(R)-2,3-dihydroxypropanal



REMINDER

A chemical name is consisted of four parts in the IUPAC Nomenclature System

IUPAC NOMENCLATURE

PREFIX PARENT LOCANT SUFFIX

indicate the location and identity of substituent(s)

Defines the main part of the molecule and indicate the longest carbon chainor the ring, etc.

identifies the primary functional group

gives the location of the primary functional group

From Fundamental of OrganicChemistry by J. McMurry




METHYLDOPA

2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid

123

4

3 12

propanoic acid

2-methyl

2-amino3-(3,4-dihydroxyphenyl)

* Substituents are written in alphabetical order


Phenylalaninederivative

49



METHYLDOPA

It is a prodrug.

Methyldopa is transported actively in the CNS by an aromatic acid transporter

system. Then, it is converted to the metabolite responsible from the activity.

This convertion is presented next slide.

.



CONVERSION OF METHYLDOPA TO ACTIVE METABOLITE

AADC

(L-Aromatic Amino Acid Decarboxylase)

Methyldopa aaaa-Methyldopamine

DBH

(Dopamine-bbbb-hydroxylase)

(1R,2S)-aaaa-Methylnorepinephrine aaaa2-agonist

active metabolite of methyldopa




Methyldopa absorption is limited and range 8% to 62%.

Its absorption appears to involve an amino acid transport system. Therefore its absorption

is affected by food and about 40% of absorbed drug is converted to O-sulfate conjugate by

the intestinal mucosal cells.

METHYLDOPA


Methydopa is used only by oral route, because its zwitterionic character limits its

solubility.

HO

HO

CH2 C

NH3

CH3

COO-

+


52


Methyldopa is unstable in the presence of oxidizing agents (also air), alkaline pH and

light.

METHYLDOPA


HO

HO

CH2 C

NH3

CH3

COO-

+

Catechol is very susceptible to oxidation



The ethyl ester of methyldopa is known as Methyldopate.

The hydrochloride salt of methyldopate is highly water soluble and developed to

make parenteral solution.

Methyldopate is hydrolyzed to methydopa in the body by esterases.

METHYLDOPA


METHYLDOPATE

Hydrochloride salt of METHYLDOPATE



Diuretics










Other Drugs




DIRECT VASODILATORS

These Drugs reduce arterial smooth muscle tone by direct action on the vasculature

without interference from the autonomic innervation.

They produce vasodilation and lower the blood tension.

They can cause increase in heart rate and cardiac output by increased sympathetic

reflex activity.

Hydralazine, dihydralazine and sodium nitroprusside are the examples of this class.



DIRECT VASODILATORS

HYDRALAZINE

benzo[d]pyridazinepyridazinebenzene

a

b

d

c

4

3

1

2

5

6

7

8

phthalazine

1-hydrazinylphthalazine

hydrazine



Synthesis of Hydralazine

DIRECT VASODILATORS

C

C

O

H

O

OH

PCl5

2-formylbenzoic acid phthalazin-1(2H)-one phthalazin-1-ol

- HCl

- 2 H2O

Added hydrogen



ADDED HYDROGEN IN NOMENCLATURE

REMINDER

‘’Added Hydrogen’’ describes hydrogen atoms added to a specific structure as a consequence of the

addition of a suffix or a prefix describing a structural modification.

This type of indicated hydrogen is normally cited in parentheses after the locant of the additional

feature.

N

pyridin-2(1H)-one

43

1

2

5

6

pyridine

4

3

1

2

5

6 NH

N

O

pyrimidin-2(1H)-onepyrimidine

From IUPAC Gold Book



HYDRALAZINE

Hydralazine acts on vascular smooth muscle to cause relaxation.

It is used orally as hydrochloride salt.

Hydralazine is metabolized by microsomal enzymes and excreted by kidneys.

DIRECT VASODILATORS



Metabolism of Hydralazine

N

N

NHNH2

OH

Benzylic

Oxidation

Acetylation

Glucuronide Formation

DIRECT VASODILATORS




Metabolism of hydralazine



DIHYDRALAZINE

DIRECT VASODILATORS

N

N

NHNH2

NHNH2

1,4-dihydrazinylphthalazine

SODIUM NITROPRUSSIDENa2Fe(CN)5NO Sodium nitroferricyanide

This drug has short duration of action.

Its use is limited to hypertensive emergencies.

It forms nitric oxide (NO).

The hypotensive effect of the drug is the result of nitric oxide.



Diuretics










Other Drugs




POTASSIUM CHANNEL AGONISTS

These drugs are also known as Potassium Channel Openers.

These agents activate ATP-sensitive K+-channels in vascular smooth muscle.

Opening potassium channels leads to a decrease of intracellular Ca+2 and results in

hyperpolarization of the membrane.

This process produces an inhibitory influence on the membrane excitation and

causes vasodilation

Minoxidil and diazoxide are the examples of this class.




DIAZOXIDE

7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide

2H-1,2,4-thiadiazine

SN

HN

1,2,4-thiadiazine

1

6

5

4

2

3

1

6

5

4

2

3

4H-1,2,4-thiadiazine

1,2,4-thiadiazine

benzo thiadiazine

12

3

45

6

78

Indicated Hydrogen

2H-1,2,4-benzothiadiazine




DIAZOXIDE

Hydrochlorothiazide

Chlorothiazide

Diureticsİt was developed to increase the antihypertansive action and

to minimize the diuretic effect (without sulfamoyl group!!)

Acidic proton

Sodium salt can be prepared




DIAZOXIDE

It is a rapidly acting antihypertensive agent for emergency reduction of blood pressure

in hospitalized patient (with accelerated or malignant hypertension) by intravenous

injection.

Water soluble sodium salt is used for injectable formulation.




MINOXIDIL

N

N

N

H2N NH2

O

1

6

54

2

3

2,6-diamino-4-(piperidin-1-yl)pyrimidine 1-oxide

piperidine

pyrimidine

N

N

N

H2N NH2

OSO3-

Minoxidil Sulfate

Prodrug

Sulfotransferaseenzyme

Active Metabolite

(in the liver)



MINOXIDIL

N

N

N

H2N NH2

O


Minoxidile is used for severe hypertension uncontrolled by other drugs. It is the only direct-acting vasodilator that requiresmetabolic activation to produce its antihypertensive effect.

It has characteristic side effects of direct vasodilatory agents such as

sodium and water retention, reflex tachycardia.

Minoxidile topical solution is used to treat alopecia androgenitica. It is believed to

increase cutaneous blood flow stimulating hair growth.

Male-pattern baldness



SYNTHESIS OF MINOXIDIL

N

N

OH

HO

HO

N

N

Cl

Cl

Cl

POCl3

NH3

2,6-diamino-4-chloropyrimidine

Barbituric acid2,4,6--trichloropyrimidine

m-chloroperbenzoic acid(MCPBA)

2,6-diamino-4-chloropyrimidine 1-oxide

Next SlidePlease




SYNTHESIS OF MINOXIDIL

2,6-diamino-4-chloropyrimidine 1-oxide

N

N

N

H2N NH2

O

Minoxidile

NH

- HCl

piperidine




Diuretics










Other Drugs




RENIN-ANGIOTENSIN SYSTEM INHIBITORS

The renin-angiotensin hormonal system plays a central role in the control of

sodium excretion and body fluid volume.

It is closely connected with sympathetic system and aldosteron secretion in the

regulation of blood pressure.




Sympathetic Stimulation

Hypotension

Decreased sodium extrection

Angiotensinogen Angiotensin I

Kidneys

A glycoprotein

Synthesized primarily in the liver

Renin (an aspartyl protease)

decapeptide




Angiotensin I Angiotensin II

Angiotension Converting Enzyme

ACE

decapeptide Octapeptide

a potent vasoconstrictor

Glu-AP

(Glutamyl aminopeptidase)

Angiotensin III

Less potent as vasoconstrictor

Significant regulatory effect on sodium excretion by renal tubes




Renin

Angiotensinogen Angiotensin I Angiotensin II

Cardiac and Vascular

Hypertrophy

Systemic

Vasocontriction

Increased Blood

Volume

Renal Sodium and

Fluid Retention

Aldosterone

Kidney

ELEVATED BLOOD

PRESSURE

Angiotension IIIACE Glu-AP


77



Renin


Cardiac and Vascular

Hypertrophy

Systemic

Vasocontriction

Increased Blood

Volume

Renal Sodium and

Fluid Retention

Aldosterone

Kidney

ELEVATED BLOOD

PRESSURE





Renin-angiotensin system inhibitors can be classified as follows

(a) Angiotension Converting Enzyme (ACE) Inhibitors

(b) Angiotension Antagonists (Angiotension AT1 Receptor Blockers)

(c) Renin Inhibitors



ACE INHIBITORS

Captopril, Lisinopril, Enalapril, Benazepril, Quinapril, Ramipril, Fosinopril and

Trandopril are the examples of Angiotension Converting Enzyme (ACE)

Inhibitors.

Enalapril, Benazepril, Quinapril, Ramipril, Fosinopril and Trandopril are

prodrugs.



ACE INHIBITORS

Because of the importance in regulating kidney function, aldosterone release,

electrolyte balance and blood volume, the renin-angiotension system is very

important drug target in the management of high blood pressure and hearth

failure.

They are used in hypertension and hearth failure

A common side effect of ACE inhibitors is a dry cough appearing in about 10%

of patients (it appears to be related to the elevation in bradykinin).



ACE INHIBITORS

CAPTOPRIL

*

*

(S)-1-((S)-3-mercapto-2-methylpropanoyl)pyrrolidine-2-carboxylic acid

Sulfhydryl group is responsible for the excellent inhibitor activity

It is also responsible two common side effects of captopril:

Skin Rashes

Taste disturbances (metallic taste, loss of taste)

First ACE inhibitor used in therapy

Common side effects of mercapto-containing

drugs (e.g. Penicillamine )



N

C

O

CH2C

CH3H

S

C

H

O

O-

Arg

CN+H2N

H

H

O

H

Zn++

HYPOTHETICAL BINDING OF CAPTOPRIL IN THE ACTIVE SITE OF ACE

Active site of ACE

Arginine residue

(cationic site)

Zinc ion

Hydrophobic pocket

Hydrogen bond

donor group


Prolin

83



David W. Cushman, Miguel A. Ondetti, Design of angiotensin converting enzyme inhibitors, Nature Medicine , Volume 5, Number 10, p.1110-1112, October 1999.

Proposed binding to the active site of ACE by a substrate or venom peptide inhibitor with terminal sequence Phe–Ala–Pro, by succinylamino acids, and by captopril.



David Cushman and Miguel Ondetti, 1977.

Prof. Dr. Erçin ERCİYAS, May 8, 2018Prof. Dr. Erçin ERCİYAS, May 8, 2018

85



CONCLUSION

The active site model that we described in our original studies used simple

chemical concepts guided by a hypothetical ‘paper and pencil’ model of

substrate and inhibitor binding to the enzyme.

This rational design approach has led to a class of structurally simple

compounds that can inhibit the action of the enzyme with great potency and

specificity, properties that translate in vivo into effective antihypertensive

activity with a remarkably low level of unwanted side effects or toxicity.



ACE INHIBITORS

LISINOPRIL

* *

*(S)-pyrrolidine-2-carboxylic acid

(R)-6-aminohexanoyl

(S)-1-carboxy-3-phenylpropyl

CAPTOPRIL



ACE INHIBITORS

* *

*

(S)-1-((R)-6-amino-2-((S)-1-carboxy-3-phenylpropyl)hexanoyl)pyrrolidine-2-carboxylic acid

LISINOPRIL



ACE INHIBITORS

SYNTHESIS OF CAPTOPRIL

+DCC

3-(acetylthio)-2-methylpropanoic acid butyl pyrrolidine-2-carboxylate

CF3COOH

NH3

CAPTOPRIL

butyl 1-(3-(acetylthio)-2-methylpropanoyl)pyrrolidine-2-carboxylate

N,N'-Dicyclohexylcarbodiimide



ACE INHIBITOR PRODRUGS

Enalapril, Benazepril, Quinapril, Ramipril, Fosinopril and Trandopril are examples

of this class.

Enalapril is the first and the prototype of this class.

These drugs do not have thiol group (no common side effects!)

Except fosinopril (containing phosphorus), all of them share the (S)-2-amino-4-

phenylbutyric acid ethyl ester moiety. Why ester formation?

(S)-ethyl 2-amino-4-phenylbutanoate




General Structure of ACE

Inhibitor Prodrugs

Metabolism by liver and intestinal enzymes

hydrolysis

Active metabolite




ENALAPRIL

(S)-pyrrolidine-2-carboxylic acid

*

*

*

((R)-1-ethoxycarbonyl-3-phenypropyl)amino

Propanoyl (propionyl)

CAPTOPRIL




ENALAPRIL

Long-acting ACE inhibitor

Maleate salt is used

(S)-1-[(S)-2-[((R)-1-ethoxycarbonyl-3-phenypropyl)amino]propanoyl]pyrrolidine-2-carboxylic

acid




ENALAPRIL

hydrolysis

ENALAPRILATProdrug

Active Metabolite

in vivo



ACE INHIBITOR PRODRUGSENALAPRIL MALEATE

Which nitrogen atom can be formed maleate salt ? Why?




BENAZEPRIL

N

H

1H-azepine

a b

1H-benzo[b]azepine

12

3

4 5 6

7

8

9

C

H2C

HC2H5OOC

CH2

NH

N

OCH2COOH

2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl]acetic acid

((R)-1-ethoxycarbonyl-3-phenypropyl)amino



2-[(S)-3-[((S)-1-ethoxycarbonyl-3-phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-

benzo[b]azepin-1-yl]acetic acid

BENAZEPRIL

C

H2C

HC2H5OOC

CH2

NH

N

OCH2COOH


BENAZAPRILAT

Active Metabolite



QUINAPRIL


1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

((S)-1-ethoxycarbonyl-3-phenylpropyl)amino

(S)-propanoyl


1

98


QUINAPRIL


(3S)-2-[(S)-2-[((S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propanoyl]-1,2,3,4-

tetrahydroisoquinoline-3-carboxylic acid

QUINAPRILATE

Active Metabolite



ANGIOTENSIN II ANTAGONISTS

These drugs are the angiotension II receptor blockers.

There are four subtypes of angiotension II receptors identified to date, namely

AT1 , AT2, AT3 and AT4

AT1 receptors of angiotension II have importance in managing spesific

cardiovascular diseases.



Stimulation of AT1 receptors of angiotension II cause

(a) vasocontriction

(b) increased aldosterone synthesis and secretion

(c) increased vasopressin secretion

(d) decreased renal blood flow

(e) increased renal tubular sodium reuptake

(f) Other physiological events





Competetive antagonists of AT1 receptors of angiotension II produce

vasodilatory effects.

These drugs are used in the treatment of hypertension and heart failure in a

similar manner as ACE inhibitors.

Because they do not inhibit ACE, they do not cause an increase in bradykinin,

which contributes to the some of the side effects of ACE inhibitors (cough and

angioedema).

Losartan, valsartan, candesartan, irbesartan and telmisartan are the

examples of this class.




General Structure for Losartan, Valsartan, Candesartan, Irbesartan and Telmisartan

Prof. Dr. Erçin ERCİYAS, May 8, 2018 104



N

NHOH2C

Cl

C4H9

CH2

N

NN

HN

LOSARTAN

2-butyl-4-chloro-1-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]imidazole-5-methanole

1

2

34

5

Losartan is the first angiotension II AT1 receptor antagonist

Potassium salt is used orally. How?? From where can it give

K salt? Brand name :Cozaar

Tetrazole ring has acidic character and

resembles the acidic function of

angiotension II during receptor

interaction.




N

NHOH2C

Cl

C4H9

CH2

N

NN

HN

LOSARTAN

Extensive first-pass metabolism

N

NHOOC

Cl

C4H9

CH2

N

NN

HN

This metabolite is closely 15 times more

potent than the parent compound

oxidation



ANGIOTENSIN II ANTAGONISTSSYNTHESIS OF LOSARTAN

(2-butyl-4-chloro-1H-imidazol-5-yl)methanol

+NaOCH3

4'-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile

N

NHOH2C

Cl

C4H9

CH2

NCNaN3

N

NHOH2C

Cl

C4H9

CH2

N

NN

HN




VALSARTAN

2-[N-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]pentanamido]-3-methylbutanoic acid



RENIN INHIBITORS

Renin


Renin is a circulating enzyme secreted by kidneys in response to decreased

glomerular filtration rate.

Inhibitors of renin, by reducing the biosynthesis of angiotension II, have usefulness

in managing cardiovascular diseases such as hypertension and heart failure .

Renin inhibitors have been investigated more than 30 years; first member of this

class, Aliskiren, has been introduced into therapy in 2007.




RENIN INHIBITORS

ALISKIREN

(5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4,5-dihydroxy-2-isopropyl-7-(4-methoxy-

3-(3-methoxypropoxy)benzyl)-8-methylnonanamide

It is the first renin inhibitor approved by FDA as hypertensive in 2007.



Diuretics










Other Drugs




CALCIUM CHANNEL BLOCKERS

Calcium Channel Blockers can be classified according to their chemical

structures as follows:

Benzothiazepine Derivatives

Diltiazem

Aralkylamine Derivatives (Diphenylalkylamine Derivatives)

Verapamil

1,4-Dihydropyridine Derivatives

Nifedipine, nicardipine amlodipine and others

The effects of these three classes on myocardium and the arteries vary from

one class to the other





Diltiazem


Verapamil


Nifedipine, nicardipine, amlodipine and others

Benzothiazepines (diltiazem) and Aralkylamines (verapamil) affect both the

hearth and arteriols

Therefore, benzothiazepines (diltiazem) and Aralkylamines (verapamil) are used

clinically as antianginal, antiarrhythmic and antihypertensive





Diltiazem


Verapamil


Nifedipine, nicardipine, amlodipine and others

Dihydropyridines have much less affect on cardiac tissues and higher

specificity for the arteriols.

Therefore, Dihydropyridines are used frequently as antianginal and

antihypertensive



CLASS IV AGENTS(CALCIUM CHANNEL BLOCKERS)

Taken from antiarrhythmic drugs section




VERAPAMIL


CLASS IV

5-((3,4-Dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile

117



VERAPAMIL

Verapamil works by relaxing the muscles of heart andblood vessels.

It has been used in the treatment of hypertension,angina pectoris, cardiac arrhythmia. It has also beenused as a vasodilator.


CLASS IV

118



DILTIAZEM


CLASS IV

119



DILTIAZEM

Diltiazem is used for treating:

Heart pain (angina),

High blood pressure,

Abnormal heart rhythms.

It is based upon a thiazepine ring.


CLASS IV

120



BEPRIDIL


CLASS IV

It has inhibitory effects on both the slow calcium and fast sodium inward currents in myocardial and vascular smooth muscle.

32

1

1

121


MISCELLANEOUS TACHYARRHTHYMİC AGENTS



ADENOSINE MISCELLANEOUS


2

1

4

56 7

9

123



R1

R2

R3

CH

OH

CH NH R5

R4

SYMPATHOMIMETIC DRUGS FOR TREATMENT OF BRADYCARDIA

Compound R1 R2 R3 R4 R5

Ephedrine

2-(methylamino)-1-phenylpropan-1-ol

-H -H -H -CH3 -CH3

Isoproterenol (isoprenaline)

1-(3,4-Dihydroxyphenyl)-2-

isopropylaminoethanol

-OH -OH -H -H -

CH(CH3)2

Metaproterenol (orciprenaline)

1-(3,5-Dihydroxyphenyl)-2-

isopropylaminoethanol

-OH -H -OH -H -

CH(CH3)2

Terbutaline

1-(3,4-Dihydroxyphenyl)-2-tert-

butylaminoethanol

-OH -H -OH -H -C(CH3)3

Prof. Dr. Erçin ERCİYAS, May 8, 2018 124

Documents

Antihypertensive Drugs May 8, 2018opencourses.emu.edu.tr/pluginfile.php/35633/mod_forum...2018/05/08 · Altan Bilgin ve Prof. Dr. Cihat Şafak (2004) in Turkish 6) Farmasötik Kimya