PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ANTIHYPERTENSIVE DRUGS
Prof. Dr. Erçin ERCİYAS
May 8, 2018
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
ANTIHYPERTENSIVE DRUGS
Prof. Dr. Erçin ERCİYAS, May 8, 20183
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
ANTIHYPERTENSIVE DRUGS
Prof. Dr. Erçin ERCİYAS, May 8, 20184
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
Prof. Dr. Erçin ERCİYAS, May 8, 20185
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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.
Prof. Dr. Erçin ERCİYAS, May 8, 20186
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BBBB-ADRENERGIC BLOCKERS
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
Prof. Dr. Erçin ERCİYAS, May 8, 20187
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BBBB-ADRENERGIC BLOCKERS
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)
Prof. Dr. Erçin ERCİYAS, May 8, 20188
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
BBBB-ADRENERGIC BLOCKERS
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
Prof. Dr. Erçin ERCİYAS, May 8, 20189
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BBBB-ADRENERGIC BLOCKERS
bbbb-Receptor Blockers are the derivatives of
(a) Aryloxypropanolamine (mostly) or
(b) Arylethanolamine
Prof. Dr. Erçin ERCİYAS, May 8, 201810
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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.
Prof. Dr. Erçin ERCİYAS, May 8, 201811
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
EXAMPLES OF BBBB-ADRENERGIC BLOCKERS
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) .
* *
Prof. Dr. Erçin ERCİYAS, May 8, 201812
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EXAMPLES OF BBBB-ADRENERGIC BLOCKERS
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
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
EXAMPLES OF BBBB-ADRENERGIC BLOCKERS
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
Prof. Dr. Erçin ERCİYAS, May 8, 201814
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PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-AUTUMN TERM
EXAMPLES OF BBBB-ADRENERGIC BLOCKERS
LABETALOL
2-hydroxybenzamide
ethyl
butyl
(salicylamide)
Prof. Dr. Erçin ERCİYAS, May 8, 2018
2-Hydroxy-5-[1-hydroxy-2-(4-phenylbutan-2-ylamino)ethyl]benzamide
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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
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EXAMPLES OF BBBB-ADRENERGIC BLOCKERS
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
Prof. Dr. Erçin ERCİYAS, May 8, 201817
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
Diuretics
Centrally Acting Sympatholytics
Adrenergic Neuron Blockers
Adrenergic Receptor Blockers
aaaa1-Adrenergic Receptor Blockers
bbbb-Adrenergic Receptor Blockers
Direct Acting Vasodilators
Potassium Channel Agonists
Renin-Angiotensin System Inhibitors
Calcium Channel Blockers
Other Drugs
CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS
Prof. Dr. Erçin ERCİYAS, May 8, 201818
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201819
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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)
aaaa1-ADRENERGIC RECEPTOR BLOCKERS
Prof. Dr. Erçin ERCİYAS, May 8, 201820
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
NONSELECTIVE aaaa-ADRENERGIC RECEPTOR BLOCKERS
aaaa1-ADRENERGIC RECEPTOR BLOCKERS
Prof. Dr. Erçin ERCİYAS, May 8, 201821
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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.
NONSELECTIVE aaaa-ADRENERGIC RECEPTOR BLOCKERS
aaaa1-ADRENERGIC RECEPTOR BLOCKERS
Prof. Dr. Erçin ERCİYAS, May 8, 201822
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
aaaa1-ADRENERGIC RECEPTOR BLOCKERS
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201823
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
aaaa1-ADRENERGIC RECEPTOR BLOCKERS
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
Prof. Dr. Erçin ERCİYAS, May 8, 2018
İupac: [4-(4-Amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(furan-2-yl)methanone
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SYNTHESIS OF PRAZOSİN
aaaa1-ADRENERGIC RECEPTOR BLOCKERS
2-amino-4,5-dimethoxybenzoic acid
Sodium cyanate
(NaOCN)
SOCl2
Thionyl chloride
Prof. Dr. Erçin ERCİYAS, May 8, 201825
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aaaa1-ADRENERGIC RECEPTOR BLOCKERS
SYNTHESIS OF PRAZOSİN (continuing)
NH3
1-(2-furoyl)piperazine
Prof. Dr. Erçin ERCİYAS, May 8, 201826
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aaaa1-ADRENERGIC RECEPTOR BLOCKERS
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
Prof. Dr. Erçin ERCİYAS, May 8, 201827
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
aaaa1-ADRENERGIC RECEPTOR BLOCKERS
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.
Prof. Dr. Erçin ERCİYAS, May 8, 2018
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
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PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
Diuretics
Centrally Acting Sympatholytics
Adrenergic Neuron Blockers
Adrenergic Receptor Blockers
aaaa1-Adrenergic Receptor Blockers
bbbb-Adrenergic Receptor Blockers
Direct Acting Vasodilators
Potassium Channel Agonists
Renin-Angiotensin System Inhibitors
Calcium Channel Blockers
Other Drugs
CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS
Prof. Dr. Erçin ERCİYAS, May 8, 201829
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
Adrenergic Neuron Blockers are comprised of two different groups:
(a) Reserpine and Derivatives
(b) Guanidine Derivatives
ADRENERGİC NEURON BLOCKERS
Prof. Dr. Erçin ERCİYAS, May 8, 201830
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201831
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ADRENERGİC NEURON BLOCKERS
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.
Prof. Dr. Erçin ERCİYAS, May 8, 2018
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ADRENERGİC NEURON BLOCKERS
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
Prof. Dr. Erçin ERCİYAS, May 8, 2018
GUANETHIDINEOcane: Suffixes for fully saturatedeight membered ring without nitrogen
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Diuretics
Centrally Acting Sympatholytics
Adrenergic Neuron Blockers
Adrenergic Receptor Blockers
aaaa1-Adrenergic Receptor Blockers
bbbb-Adrenergic Receptor Blockers
Direct Acting Vasodilators
Potassium Channel Agonists
Renin-Angiotensin System Inhibitors
Calcium Channel Blockers
Other Drugs
CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS
Prof. Dr. Erçin ERCİYAS, May 8, 201834
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201835
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
CLONIDINECENTRALLY ACTING SYMPATHOLYTIC DRUGS
1H-Imidazole
NH
NHN
Cl
Cl
4 3
1
25
NH
NH
2,3-dihydro-1H-imidazole(4-imidazoline)
4,5-dihydro-1H-imidazole(2-imidazoline)
NH
NH
REMINDER
Imidazolidine
Indicated Hydrogen
Prof. Dr. Erçin ERCİYAS, May 8, 201836
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
2,3-dihydro-1H-imidazole(4-imidazoline)
4,5-dihydro-1H-imidazole(2-imidazoline)
REMINDER
indicate the saturated positions
indicate double bond’s position
Prof. Dr. Erçin ERCİYAS, May 8, 201837
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
Prof. Dr. Erçin ERCİYAS, May 8, 201838
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
NH2
ClCl NH4SCN
CH3I
SYNTHESIS OF CLONIDINE
(Ammonium thiocyanate)
2,6-dichlorophenylthiourea
2,6-dichlorophenyl-S-methylisothiourea
2,6-dichloroaniline
- HI
Prof. Dr. Erçin ERCİYAS, May 8, 201839
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
H2NCH2CH2NH2N
Cl
Cl
C
SCH3
NH
H-CH3SH
-NH3NH
NHN
Cl
Cl
SYNTHESIS OF CLONIDINE
CENTRALLY ACTING SYMPATHOLYTIC DRUGS
CLONIDINE
N
CH2
CH2
N
H
H
H
H
+
2,6-dichlorophenyl-S-methylisothiourea
Prof. Dr. Erçin ERCİYAS, May 8, 201840
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
CLONIDINE
CENTRALLY ACTING SYMPATHOLYTIC DRUGS
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
Prof. Dr. Erçin ERCİYAS, May 8, 201841
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
CLONIDINE
CENTRALLY ACTING SYMPATHOLYTIC DRUGS
As a centrally acting drug, at physiological pH,
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
Prof. Dr. Erçin ERCİYAS, May 8, 201842
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
CLONIDINE
NH
HN
N
Cl
Cl
CENTRALLY ACTING SYMPATHOLYTIC DRUGS
As a centrally acting drug, at physiological pH,
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
Prof. Dr. Erçin ERCİYAS, May 8, 2018
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GUANABENZ
CENTRALLY ACTING SYMPATHOLYTIC DRUGS
GUANFACINE
Prof. Dr. Erçin ERCİYAS, May 8, 2018
2-[(E)-(2,6-dichlorophenyl)methylideneamino]guanidine
N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide
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GUANABENZ
CENTRALLY ACTING SYMPATHOLYTIC DRUGS
GUANFACINE
Guanidine
CLONIDINE
CLONIDINE GUANABENZGUANFACINE> >Elimination half-life is decreasing
20-25h 17h 3h
Prof. Dr. Erçin ERCİYAS, May 8, 201845
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CENTRALLY ACTING SYMPATHOLYTIC DRUGS
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
?
Prof. Dr. Erçin ERCİYAS, May 8, 201846
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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
Prof. Dr. Erçin ERCİYAS, May 8, 201847
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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
Prof. Dr. Erçin ERCİYAS, May 8, 201848
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CENTRALLY ACTING SYMPATHOLYTIC DRUGS
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
Prof. Dr. Erçin ERCİYAS, May 8, 2018
Phenylalaninederivative
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CENTRALLY ACTING SYMPATHOLYTIC DRUGS
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.
.
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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
CENTRALLY ACTING SYMPATHOLYTIC DRUGS
Prof. Dr. Erçin ERCİYAS, May 8, 201851
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
CENTRALLY ACTING SYMPATHOLYTIC DRUGS
Methydopa is used only by oral route, because its zwitterionic character limits its
solubility.
HO
HO
CH2 C
NH3
CH3
COO-
+
Prof. Dr. Erçin ERCİYAS, May 8, 2018
52
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
Methyldopa is unstable in the presence of oxidizing agents (also air), alkaline pH and
light.
METHYLDOPA
CENTRALLY ACTING SYMPATHOLYTIC DRUGS
HO
HO
CH2 C
NH3
CH3
COO-
+
Catechol is very susceptible to oxidation
Prof. Dr. Erçin ERCİYAS, May 8, 201853
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
CENTRALLY ACTING SYMPATHOLYTIC DRUGS
METHYLDOPATE
Hydrochloride salt of METHYLDOPATE
Prof. Dr. Erçin ERCİYAS, May 8, 201854
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
Diuretics
Centrally Acting Sympatholytics
Adrenergic Neuron Blockers
Adrenergic Receptor Blockers
aaaa1-Adrenergic Receptor Blockers
bbbb-Adrenergic Receptor Blockers
Direct Acting Vasodilators
Potassium Channel Agonists
Renin-Angiotensin System Inhibitors
Calcium Channel Blockers
Other Drugs
CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS
Prof. Dr. Erçin ERCİYAS, May 8, 201855
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201856
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
DIRECT VASODILATORS
HYDRALAZINE
benzo[d]pyridazinepyridazinebenzene
a
b
d
c
4
3
1
2
5
6
7
8
phthalazine
1-hydrazinylphthalazine
hydrazine
Prof. Dr. Erçin ERCİYAS, May 8, 201857
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
Prof. Dr. Erçin ERCİYAS, May 8, 201858
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
Prof. Dr. Erçin ERCİYAS, May 8, 201859
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
Prof. Dr. Erçin ERCİYAS, May 8, 201860
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
Metabolism of Hydralazine
N
N
NHNH2
OH
Benzylic
Oxidation
Acetylation
Glucuronide Formation
DIRECT VASODILATORS
Prof. Dr. Erçin ERCİYAS, May 8, 201861
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
Metabolism of hydralazine
Prof. Dr. Erçin ERCİYAS, May 8, 201862
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201863
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
Diuretics
Centrally Acting Sympatholytics
Adrenergic Neuron Blockers
Adrenergic Receptor Blockers
aaaa1-Adrenergic Receptor Blockers
bbbb-Adrenergic Receptor Blockers
Direct Acting Vasodilators
Potassium Channel Agonists
Renin-Angiotensin System Inhibitors
Calcium Channel Blockers
Other Drugs
CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS
Prof. Dr. Erçin ERCİYAS, May 8, 201864
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201865
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
POTASSIUM CHANNEL AGONISTS
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
Prof. Dr. Erçin ERCİYAS, May 8, 201866
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
POTASSIUM CHANNEL AGONISTS
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
Prof. Dr. Erçin ERCİYAS, May 8, 201867
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
POTASSIUM CHANNEL AGONISTS
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201868
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
POTASSIUM CHANNEL AGONISTS
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)
Prof. Dr. Erçin ERCİYAS, May 8, 201869
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
MINOXIDIL
N
N
N
H2N NH2
O
POTASSIUM CHANNEL AGONISTS
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
Prof. Dr. Erçin ERCİYAS, May 8, 201870
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
POTASSIUM CHANNEL AGONISTS
Prof. Dr. Erçin ERCİYAS, May 8, 201871
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
SYNTHESIS OF MINOXIDIL
2,6-diamino-4-chloropyrimidine 1-oxide
N
N
N
H2N NH2
O
Minoxidile
NH
- HCl
piperidine
POTASSIUM CHANNEL AGONISTS
Prof. Dr. Erçin ERCİYAS, May 8, 201872
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
Diuretics
Centrally Acting Sympatholytics
Adrenergic Neuron Blockers
Adrenergic Receptor Blockers
aaaa1-Adrenergic Receptor Blockers
bbbb-Adrenergic Receptor Blockers
Direct Acting Vasodilators
Potassium Channel Agonists
Renin-Angiotensin System Inhibitors
Calcium Channel Blockers
Other Drugs
CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS
Prof. Dr. Erçin ERCİYAS, May 8, 201873
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201874
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
RENIN-ANGIOTENSIN SYSTEM INHIBITORS
Sympathetic Stimulation
Hypotension
Decreased sodium extrection
Angiotensinogen Angiotensin I
Kidneys
A glycoprotein
Synthesized primarily in the liver
Renin (an aspartyl protease)
decapeptide
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PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
RENIN-ANGIOTENSIN SYSTEM INHIBITORS
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
Prof. Dr. Erçin ERCİYAS, May 8, 201876
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
RENIN-ANGIOTENSIN SYSTEM INHIBITORS
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
Prof. Dr. Erçin ERCİYAS, May 8, 2018
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PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
RENIN-ANGIOTENSIN SYSTEM INHIBITORS
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
Prof. Dr. Erçin ERCİYAS, May 8, 201878
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
RENIN-ANGIOTENSIN SYSTEM INHIBITORS
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
Prof. Dr. Erçin ERCİYAS, May 8, 201879
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201880
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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).
Prof. Dr. Erçin ERCİYAS, May 8, 201881
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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 )
Prof. Dr. Erçin ERCİYAS, May 8, 201882
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
Prof. Dr. Erçin ERCİYAS, May 8, 2018
Prolin
83
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PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201884
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
David Cushman and Miguel Ondetti, 1977.
Prof. Dr. Erçin ERCİYAS, May 8, 2018Prof. Dr. Erçin ERCİYAS, May 8, 2018
85
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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.
Prof. Dr. Erçin ERCİYAS, May 8, 201886
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ACE INHIBITORS
LISINOPRIL
* *
*(S)-pyrrolidine-2-carboxylic acid
(R)-6-aminohexanoyl
(S)-1-carboxy-3-phenylpropyl
CAPTOPRIL
Prof. Dr. Erçin ERCİYAS, May 8, 201887
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ACE INHIBITORS
* *
*
(S)-1-((R)-6-amino-2-((S)-1-carboxy-3-phenylpropyl)hexanoyl)pyrrolidine-2-carboxylic acid
LISINOPRIL
Prof. Dr. Erçin ERCİYAS, May 8, 201888
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
Prof. Dr. Erçin ERCİYAS, May 8, 201889
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
Prof. Dr. Erçin ERCİYAS, May 8, 201890
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ACE INHIBITOR PRODRUGS
General Structure of ACE
Inhibitor Prodrugs
Metabolism by liver and intestinal enzymes
hydrolysis
Active metabolite
Prof. Dr. Erçin ERCİYAS, May 8, 201891
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ACE INHIBITOR PRODRUGS
ENALAPRIL
(S)-pyrrolidine-2-carboxylic acid
*
*
*
((R)-1-ethoxycarbonyl-3-phenypropyl)amino
Propanoyl (propionyl)
CAPTOPRIL
Prof. Dr. Erçin ERCİYAS, May 8, 201892
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ACE INHIBITOR PRODRUGS
ENALAPRIL
Long-acting ACE inhibitor
Maleate salt is used
(S)-1-[(S)-2-[((R)-1-ethoxycarbonyl-3-phenypropyl)amino]propanoyl]pyrrolidine-2-carboxylic
acid
Prof. Dr. Erçin ERCİYAS, May 8, 201893
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ACE INHIBITOR PRODRUGS
ENALAPRIL
hydrolysis
ENALAPRILATProdrug
Active Metabolite
in vivo
Prof. Dr. Erçin ERCİYAS, May 8, 201894
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ACE INHIBITOR PRODRUGSENALAPRIL MALEATE
Which nitrogen atom can be formed maleate salt ? Why?
Prof. Dr. Erçin ERCİYAS, May 8, 201895
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ACE INHIBITOR PRODRUGS
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
Prof. Dr. Erçin ERCİYAS, May 8, 201896
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
ACE INHIBITOR PRODRUGS
BENAZAPRILAT
Active Metabolite
Prof. Dr. Erçin ERCİYAS, May 8, 201897
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
QUINAPRIL
ACE INHIBITOR PRODRUGS
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
((S)-1-ethoxycarbonyl-3-phenylpropyl)amino
(S)-propanoyl
Prof. Dr. Erçin ERCİYAS, May 8, 2018
1
98
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
QUINAPRIL
ACE INHIBITOR PRODRUGS
(3S)-2-[(S)-2-[((S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propanoyl]-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic acid
QUINAPRILATE
Active Metabolite
Prof. Dr. Erçin ERCİYAS, May 8, 201899
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
RENIN-ANGIOTENSIN SYSTEM INHIBITORS
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
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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.
Prof. Dr. Erçin ERCİYAS, May 8, 2018101
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
ANGIOTENSIN II ANTAGONISTS
Prof. Dr. Erçin ERCİYAS, May 8, 2018102
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ANGIOTENSIN II ANTAGONISTS
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.
Prof. Dr. Erçin ERCİYAS, May 8, 2018103
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
General Structure for Losartan, Valsartan, Candesartan, Irbesartan and Telmisartan
Prof. Dr. Erçin ERCİYAS, May 8, 2018 104
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ANGIOTENSIN II ANTAGONISTS
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.
Prof. Dr. Erçin ERCİYAS, May 8, 2018105
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ANGIOTENSIN II ANTAGONISTS
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
Prof. Dr. Erçin ERCİYAS, May 8, 2018106
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
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
Prof. Dr. Erçin ERCİYAS, May 8, 2018107
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
ANGIOTENSIN II ANTAGONISTS
VALSARTAN
2-[N-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]pentanamido]-3-methylbutanoic acid
Prof. Dr. Erçin ERCİYAS, May 8, 2018108
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
RENIN-ANGIOTENSIN SYSTEM INHIBITORS
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
Prof. Dr. Erçin ERCİYAS, May 8, 2018109
PHAR406 PHARMACEUTICAL CHEMISTRY IVEMU-SPRING TERM
RENIN INHIBITORS
Renin
Angiotensinogen Angiotensin I Angiotensin II
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.
Angiotension IIIACE Glu-AP
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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.
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Diuretics
Centrally Acting Sympatholytics
Adrenergic Neuron Blockers
Adrenergic Receptor Blockers
aaaa1-Adrenergic Receptor Blockers
bbbb-Adrenergic Receptor Blockers
Direct Acting Vasodilators
Potassium Channel Agonists
Renin-Angiotensin System Inhibitors
Calcium Channel Blockers
Other Drugs
CLASSIFICATION OF THE ANTIHYPERTENSIVE DRUGS
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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
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CALCIUM CHANNEL BLOCKERS
Benzothiazepine Derivatives
Diltiazem
Aralkylamine Derivatives (Diphenylalkylamine Derivatives)
Verapamil
1,4-Dihydropyridine Derivatives
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
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CALCIUM CHANNEL BLOCKERS
Benzothiazepine Derivatives
Diltiazem
Aralkylamine Derivatives (Diphenylalkylamine Derivatives)
Verapamil
1,4-Dihydropyridine Derivatives
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
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CLASS IV AGENTS(CALCIUM CHANNEL BLOCKERS)
Taken from antiarrhythmic drugs section
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VERAPAMIL
Prof. Dr. Erçin ERCİYAS, May 8, 2018
CLASS IV
5-((3,4-Dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile
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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.
Prof. Dr. Erçin ERCİYAS, May 8, 2018
CLASS IV
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DILTIAZEM
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CLASS IV
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DILTIAZEM
Diltiazem is used for treating:
Heart pain (angina),
High blood pressure,
Abnormal heart rhythms.
It is based upon a thiazepine ring.
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CLASS IV
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BEPRIDIL
Prof. Dr. Erçin ERCİYAS, May 8, 2018
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
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MISCELLANEOUS TACHYARRHTHYMİC AGENTS
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ADENOSINE MISCELLANEOUS
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2
1
4
56 7
9
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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
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