ASPEK STEREOKIMIA OBAT TERHADAP

BIOAKTIVITASNYA

Algafari Bakti Manggara, Ph.D

S1 Farmasi
IIK Bhakta
Structure-physiochemical
properties:
 Water solubility, partition coefficient, …
 Stereochemistry  biomolecules (reseptors,
enzymes)

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Thalidomide cases
 In 1960s in Europe, racemic
thalidomide was given to pregnant
females to cure morning sickness.
 This led to deformations in babies and
neurotoxic effects. These were due to S-
thalidomide.
 R-thalidomide contained the
desired therapeutic activity

(Bahasa Latin Rectus = kanan, Sinister = kiri)

Jika searah jarum jam, maka konfigurasinya

adalah R, jika berlawanan arah konfigurasi S
Bold : didepan bidang datar
Putus2 : dibelakang bidang datar
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Importance of steric
properties
 In pharmaceutical industries,
56% of the drugs currently in
use are chiral molecules
and 88% of the last ones are
marketed as racemates (or
racemic mixtures), consisting of
an equimolar mixture of two
enantiomers.
 In biological system there is also
a preference of a specific
stereoisomer.

Enansiomer : salah satu dari dua stereoisomer adalah bayangan cermin satu
sama lain yang non-superposabel (tidak identik), seperti tangan kiri dan kanan
Stereoisomer : senyawa berlainan yang mempunyai struktur sama, berbeda
hanya dalam hal penataan atom-atom dalam ruangan
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Example #1:

 Amino acids: 20 amino acids (exc. glycine) have

L- and D- forms, only the L- form is proteogenic

Memutar bidang polarisasi ke kanan : dekstrorotar, d, (+)

Memutar bidang polarisasi ke kiri : levorotari, l, (-)
Proteogenic : asam amino esensial yang penyusun protein

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Example #2:
 Sugars: most sugars (e.g. glucose, fructose) occur
naturally as the D-form

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Constitutional isomers
CH 3 CH 3
 Functional group: NH 2 HN O
Same molecular formula, but
different functional groups,
e.g., n-propanol and methyl O
O OCH 2 CH 3
ethyl ether
3,4-MDA phenacetin
(Ecstasy) (analgesic)

 Positional: Ph COOEt Ph
Same molecular formula,
COOEt
same functional groups, but
N N
different positions of
CH 3 CH3
functional groups, e.g., n- Mepiri
propanol, 2-propanol dine (not analgesic)
(Analge
sic)
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 Constitutional isomers
 Geometric (cis/trans): Same molecular formula,
same functional groups, same positions, but different
orientation around a double bond or on a ring.

isomer trans, atau E, dari triprolidine 1000 kali lebih kuat dari isomer
cis, atau Z sebagai antagonis H1-histamin

Antihistamin atau antagonis histamin adalah golongan obat yang digunakan untuk
mengobati gejala akibat reaksi alergi, seperti rhinitis alergi, urtikaria, dermatitis,
dan konjungtivis. 9
 Stereoisomer

s
Enantiomers: pair of stereoisomers that are related to each other as
non-super-imposable mirror image isomers
 Diastereomers: pair of stereoisomers containing more than one chiral
center and are not mirror images of each other

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Enantiomers: non-superimposible mirror images

R = Rectus
S = Sinister

Bayangan dari cermin yang tidak bisa dihimpitkan 11

Diastereomers: stereoisomers that are not mirror
images

L-erythrose L-threose

has both S configuration has the R configuration at

at C2 and C3 C2 and the S configuration
at C3

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Chiral center

Chiral molecules usually

contain at least one carbon atom
with four non-identical
substituents.

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Identification of chiral centers

 Chiral centers: carbon, nitrogen, phosphorus

OMe
MeO O O H 3C
+ * O N+ OMe
N O *
MeO
CH 3

MeO
OMe
OMe
OMe
Atracurium besylate (neuromuscular blocking agent)

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Identification of chiral centers

 Chiral centers: carbon, nitrogen, phosphorus

NH2 O O *
HO * *
OH CH3
* N
HO HO * * *
OH
Nor-epinephrine
Ph
H3 C
* O
CH 3 warfarin N
* quinine
H3 C *
CH 3
* * * HO
* H3 C
*
HO 14R
cholesterol O
13S
H 9R
5R
6S N
CH 3
HO
morphine
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Role of functional groups:

 Each functional group has a finite size or steric

dimension that contributes to the overall conformation or
three-dimensional shape of drug molecule.
 The size and shape of each functional group must be able
to be accommodated for by the binding sites present
at its biological target.
 Example:

ethyl bromide isopropyl bromide t-butyl bromide

attack is easy attack is possible attack is imposible
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Steric effects on drug
molecule:
 Increased selectivity for its biological target
 Enhanced binding interactions with its
biological target
 Favorable alteration of its rate of
metabolism.

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 Peningkatan selektivitas untuk target biologisnya

Atenolol (Farnormin, Albuterol (Ventolin), a

Internolol), a selective 1 receptor
antagonist, diindikasikan untuk
terapi angina pectoris/nteri dada,
infark miokard/serangan jantung
akut, dan hipertensi.
selective 2 receptor agonist,
diindikasikan untuk meredakan
serangan asma pada usia 4 tahun
ke atas

Agonis adalah obat yang berikatan dengan reseptor, menghasilkan respons serupa terhadap
bahan kimia dan reseptor yang dituju. Sedangkan antagonis adalah obat yang berikatan dengan
reseptor baik di situs primer, atau di situs lain, yang semuanya menghentikan reseptor untuk
menghasilkan respons
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Peningkatan interaksi pengikatan dengan target
biologisnya

diclofenac fenoprofen

Albuterol obat anti nyeri

Diclofenac (Cataflam), obat
golongan NSAID dengan
anti nyeri golongan NSAID dengan
mekanisme kerja sebagai
mekanisme kerja sebagai
cyclooxygenase (COX-2)
cyclooxygenase (COX-2) inhibitor.
inhibitor.

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Perubahan yang menguntungkan pada
laju metabolismenya

Neurotransmiter / zat
Obat sulit berkemih
penghantar rangsangan syaraf

Antibiotik Antibiotik 20
 Importance of
stereochemistry
 Efficacy, adverse effects, and toxicity of drugs may be
enantiospecific
Example #1: Atorvastatin, fluvastatin, and rosuvastatin
(anti-hypercholesterolemia) exist in four optical forms, but
they are currently used as enantiopure drugs, i.e., only
one single enantiomer.

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 Importance of
stereochemistry
 Example #2: Ephedrine
(S) CH 2 Ph
(R) CH 2 Ph
MeNH H
H
CH 3

I NHMe
Methamphetamine CH 3
10X more potent
CNS (sistem saraf II
pusat) stimulant desoxyephedri
Less cardiovascular ne  Example #3:

NH2 NH2

O N O N
R S S S
Ph CH3 Ph CH3

Cis-4-methylaminorex
Potent amphetamine
psychostimulant

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Channel blockers

 Calcium channel blockers prevent calcium from entering

cells of the heart and blood vessel walls, resulting in lower
blood pressure.
 Example #1: Diltiazem and verapamil are both chiral,
possessing asymmetric centers.
 In each case, the D-enantiomer is approximately 10 times
more potent as a calcium channel blocker than L-enantiomer

Calcium channel blocker atau antagonis kalsium merupakan obat yang

menghambat arus ion kalsium masuk ke membran sel jantung dan otot polos
pada pembuluh darah.

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 Amlodipine is used therapeutically as a racemic mixture, composed of S-
and R-enantiomers, but its calcium channel-blocking effect is confined to
S-amlodipine; R-amlodipine has 1000-fold less activity than its S-
enantiomer.
 The affinity of its L-enantiomer to the calcium channels is 1,000 times
superior to that of its dextrorotary D-enantiomer.

Calcium channel blocker atau antagonis kalsium merupakan obat yang

menghambat arus ion kalsium masuk ke membran sel jantung dan otot polos
pada pembuluh darah. 24
Receptors/enzymes
 Reseptor biologis (termasuk enzim) untuk obat bersifat kiral,
mereka hanya merespons satu isomer suatu ligan/obat.
 Isomer dengan aktivitas biologis yang diinginkan disebut eutomer
dan isomer lainnya disebut distomer

Easson-Stedman
hypothetical interaction
between the two
enantiomers of a racemic
drug with a receptor at the
drug binding sites.

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Receptors/enzymes
 Amino acid: in an
enzymatic reaction, the amino
acid has to bind with the specific
binding site before catalysis. Thus
enzymatic reaction is always
stereoisomer specific.
 The biological receptors
(including enzymes) for drugs
are chiral. Therefore they
respond to only one isomer of
a ligand/drug.

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Anaesthesia

 More than half of the synthetic agents used in

anaesthesia practice are chiral drugs.
 Almost all are administered as racemic mixture,
rather than as single pure enantiomers.
 Examples:
- inhalational general anaesthetics (e.g. isoflurane),
- intravenous anaesthetics (e.g. etomidate,
thiopentone),
- neuromuscular blocking agents (e.g.
cisatracurium)
- local anaesthetics (e.g. ropivacaine and
levobupivacaine)
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Etomidate

 Administered as a single
isomer: R-isomer
 Site of action: GABA
receptor.
 R-isomer is 15 times more
potent than the S-isomer.
etomidate
 S-isomer lacks hypnotic
activity.

Gamma-aminobutyric acid (GABA) adalah

neurotransmitter yang bertugas mengatur suasana hati

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Ketami
n
 S-ketamine is 2-4 times more
potent than R-ketamine as an
anaesthetic and analgesic agent.
 R-ketamine: emerge reactions like
hallucinations, vivid dreams and
agitation
 Metabolism of S-ketamine by liver
microsomes is 20% greater than R-
ketamine and 10% greater than the ketamin
racemate, faster clearance of the drug.

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Isoflurane

 S(+)-isoflurane reported to be
50% more potent than R(-)-
isoflurane
 Both enantiomers are equally
soluble in the lipid bilayers.
isoflurane
 S-isoflurane induced about 50%
longer sleep times than R-
isoflurane
 Majority of the inhalational
agents currently used are chiral
except, sevoflurane
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Adrenaline
 The (-) enantiomers exert stronger effect i.e; heart
rate increases
 X-ray crystallography of adrenaline Enantiomers shown that
negative form has R configuration and the positive form has
S configuration

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Neuromuscular blocking agents:
atracurium
 Intermediate duration non-depolarizing neuromuscular
blocker.
 Causes histamine release, transient hypotension,
tachycardia, facial or truncal flushing.
 Contains 4 chiral centres and is a mixture of 10 optical
and geometric isomers.

atracurium

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Potential advantages of single
enantiomer products

 Profil farmakodinamik yang kurang kompleks dan

lebih selektif
 Potensi untuk peningkatan indeks terapeutik
 Profil farmakokinetik yang kurang kompleks
 Mengurangi potensi interaksi obat yang kompleks
 Hubungan yang tidak terlalu rumit antara konsentrasi
dan efek plasma

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Absorption and
stereoselectivity
 Untuk sebagian besar obat rasemat, penyerapan
tampaknya terjadi melalui difusi pasif, asalkan tidak ada
stereoselektivitas

higher conc.

lower conc.

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Carrier mediated
transporter
 Stereo selective
intestinal transporter is the
main cause for marked
differences in the oral
absorption of enantiomers.
 L-Methotrexate have 40
fold higher Cmax and AUC
than D-Methotrexate.

methotrexate

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Distribution

 Pengikatan oleh protein plasma stereoselectivity

dapat mempengaruhi distribusi dan eliminasi
karena penentu utama distribusi dan eliminasi obat
adalah pengikatan protein.
 Enantiomer mungkin menampilkan besaran
stereoselektivitas yang berbeda antara berbagai
protein yang ditemukan dalam plasma

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Example:

 R-propranolol binding to
albumin is greater than S-
propranolol and the opposite is
observed for 1–acid glycoprotein
(AAG)
 R-propranolol: highly albumin
bound, less potent
 S-propranolol: highly bound to
AAG, available as unbound, 40-
100 time more potent
p
r
o 37
 Potency of some racemic drugs
(l = levorotary, d = dextrorotary)

Source: Lien Ai Nguyen, et al. International journal of Biomedical science

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Example of novel enantiomer drugs

 Bedaquiline (Sirturo,
TMC207 or R207910) by
Johnson & Johnson has been
approved by Food Drug
Administration as new anti-
tuberculosis drug in December
2012.
 Ini adalah pengobatan baru
untuk tuberkulosis yang
resistan terhadap banyak
obat yang dapat digunakan
sebagai alternatif ketika obat
lain gagal. Penelitian lebih
lanjut diperlukan untuk
menilai aktivitas relatif kedua
enansiomer. 39
Example of novel enantiomer drugs

 R-Tafluprost (Zioptan) by
Merck used for management of
ocular hypertension has been
approved by FDA in 2012.

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Example of novel enantiomer drugs

 R(-)-Alogliptin by Takeda
Pharmaceuticals America, Inc.
has been approved by FDA as
an adjunct to diet and exercise
to improve glycemic control in
adults with type 2 diabetes
mellitus) in 2013.

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Example of novel enantiomer drugs

 Mefloquine by Hoffman-
LaRoche Swiss is currently
manufactured and sold as a
racemate of the (R,S)- and
(S,R)- enantiomers
 (+)-Mefloquine is more
effective in treating malaria,
and the (–)-Mefloquine
specifically binds to adenosine
receptors in the central nervous
system, which may explain
some of its psychotropic effects

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Terimakasih

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