Study Guide
Introduction to Medicinal Chemistry
-
University:
Kentucky State University -
Course:
CHE 102 | Organic Chemistry II Academic year:
2024
-
Views:
423
Pages:
92
Author:
Interpoluium
Introduction to Medicinal
Chemistry
2 • What do you think you will learn in this course?
• If you want to give a word unique for medicinal chemistry course, what would
you choose?
• Give a simple definition for medicinal chemistry
3 Medicinal Chemistry: Understanding of drug chemistry
• Medicinal chemistry: the science that deals with the relationship
between the chemical structure of the drug and its behavior
in the biological systems, added to this the aspects of drug
design and synthesis.
Biological activity
Chemical structure of a drug
(organic functional groups,
stereochemistry)
Physicochemical properties of
4
the drug
These properties influence the
ADME and toxicity of the drug • What medicinal chemists can do?
5 Generally medicinal chemists can:
• Make new compounds.
• Determine their effect on biological processes.
• Alter the structure of the compound for optimum effect and
minimum side effects.
• Study absorption, distribution, metabolism and excretion of
drugs.
6 Medicinal chemistry in clinical
practice
Case study
7 This paper demonstrates how critical clinical decisions can be
addressed using medicinal chemistry knowledge. While such
knowledge may not explain all clinical decisions, medicinal
chemistry concepts are essential for the education of pharmacy
students to explain drug action in general and clinical decisions.
8 Case report 1: Propranolol-induced psychosis
A 21-year old man with a history of migraine was treated with oral propranolol for 9 months. This
gave inadequate prophylaxis and the dose was therefore increased.
No further attacks occurred. After several weeks at the higher dose he began to experience visual
hallucinations involving spiders, auditory hallucinations in which a voice whispered his name,
vivid, recurrent nightmares, depressed mood with suicidal impulses, and personality change with
odd behavior and violent outbursts. He had no previous psychiatric history and an eventempered, outgoing premorbid personality. On admission to the hospital, propranolol was
discontinued and his symptoms improved markedly. Physical examination was normal, and no
other medication was given. Electroencephalogram and skull radiograph were normal, as well as
hematological and biochemical investigations.
He remained improved for 5 more days before discharge.”
Propranolol (Aryloxypropanolamine)
Non-selective Beta adrenergic blocker
Has CNS side effects…blocking
of beta-2 receptors centrally
9 Case report 1: Propranolol-induced psychosis
10 Drug’s biological activity
Drug’s biological activity, depends on two events:
1- Reaching the site of action (pharmacokientic phase):
Governed by absorption and distribution which in turn are
governed by physicochemical properties of the drug.
2- Interacting with the site of action (pharmacodynamic
phase): Governed by the chemical structure of the drug.
For an orally administered drug the disintegration of a tablet or
capsule in the GIT, the release of the drug and its dissolution is
considered the first event (phase) and called pharmaceutical
phase.
11 Pharmacokientics of drugs
What the body does to the drug?
12 Pharmacokientics (ADME)
• Absorption (A): process by which the drug is transported into
the systemic circulation across biological membranes.
• Distribution (D): process by which a drug is transported from
systemic circulation across biological membranes.
• Metabolism (M): chemical modification of the drug at different
sites of the body in order to excrete it outside of the body.
• Elimination (E): process by which the drug or modified drug is
discarded outside body.
13 Drug
Drug
Gut
contents
Plasma
Absorption
Drug
Drug
Plasma
Cell
Distribution
14 Drug Absorption
• The most common and convenient route for drug administration
is the oral one.
• Oral absorption will be discussed in some details and many of
the principles discussed here can be applied to other routes.
• Factors affecting the absorption via GIT:
1. Biomembranes
2. pH
3. Blood flow to the absorption site
4. Surface Area [SA]
5. Contact time at the absorption site
6. Enzymes
15 Drug Absorption/ Oral absorption
Factors affecting the absorption via GIT:
1. Biomembranes: Lipid bilayer composed of phospholipids,
cholesterol and other components that make it lipophilic. They
act as barriers to the movement of drugs within the body
16 2. pH: affect mainly the ionizability and chemical stability. Most
drugs are either weak acids or weak bases. A drug passes
through membranes more readily if it is uncharged.
17 3. Blood flow to the absorption site: Because blood flow to the
intestine is much greater than the flow to the stomach, absorption
from the intestine is favored over that from the stomach.
4. Surface Area [SA]: intestine has villi and microvilli that
increase the SA dramatically compared to other site of absorption.
With a surface rich in brush borders containing microvilli, the
intestine has a surface area about 1000-fold that of the stomach,
making absorption of the drug across the intestine more efficient.
18 5. Contact time at the absorption surface: If a drug moves
through the GI tract very quickly, as can happen with severe
diarrhea, it is not well absorbed. Conversely, anything that delays
the transport of the drug from the stomach to the intestine delays
the rate of absorption of the drug.
6. Enzymes: might degrade the drugs before being absorbed.
19 Mechanisms of Drug Absorption
1. Passive Diffusion:
• From a region of higher concentration to a region of lower
concentration (down concentration gradient)
• It depends mainly on lipophilicity (partitioning) and the
concentration gradient.
• From GIT to the Blood, so the
concentration in the blood is near
to zero, so the gradient is a
continuous process.
20 • Most (many) drugs cross biologic membranes by passive
diffusion.
• Lipid soluble drugs such as ibuprofen can passively diffuse
through cell membrane (diffuse through lipid bilayer).
Ibuprofen
21 In facilitated diffusion
• a drug carrier (transmembrane protein) is required
• no energy is needed
• and the process is saturable;
• The transport of solute through membrane is down its
concentration gradient
• Examples of compounds that are absorbed by this
mechanism vitamin B1, B2 & B12, glucose and fructose.
22 facilitated diffusion
Vitamin B12
Glucose
23 2. Active transport
• Transport systems involve a carrier molecule
• Mainly to transport highly polar endogenous compounds such
as amino acids and nucleic acids
• The main factor of transport depends on the structure of the
drug.
• It is characterized by consuming energy
• It is saturable process (it may involve transport against a
concentration gradient).
• Polar drugs that bear structural resemblance to one of the
endogenous building blocks (e.g. amino acids, nucleic acid
bases, peptides) may be absorbed by this mechanism.
24 25 Levodopa
Dopamine
• Levodopa is a prodrug for the neurotransmitter dopamine.
• Dopamine is too polar to cross the blood-brain barrier so it can’t
be used. But levodopa is even more polar!! So how does it get
absorbed?!!
• Levodopa resembles phenylalanine, therefore it utilises the
transport protein for amino acids to carry it across the cell
membrane. Once in the brain, dopa decarboxylase enzyme
removes the carboxyl group and generates dopamine.
Levodopa
• You have to know
the structures of the
essential
amino
acids
14 3. Pinocytosis: the drug is engulfed by the cell membrane and a
membrane-bound vesicle is pinched off to carry the drug
across the cell which then fuses with the membrane to release
the drug from the other side of the cell. Occasionally, polar
drugs with high molecular weight such as insulin and fat
soluble vitamins (A,D,E and K) can cross the cells of the gut
via pinocytosis.
27 3. Pinocytosis:
HO
OH
O
Vit. A
Vit. E
H
OH
O
H
HO
Vit. D
OH
O
Vit. K
28 4. Ion-Pair Absorption: highly ionized (charged) molecules
such as quaternary ammonium compounds can be absorbed
via ion-pair mechanism (in the presence of negatively charged
ions) by forming an ion-pair of neutral properties with
endogenous ions which have both the required lipophilicity and
aqueous solubility for passive transport.
29 • An example of this mechanism is propranolol, a basic drug that
forms an ion-pair with oleic acid.
Propranolol
Oleic acid
30 5. Connective Absorption: movement of drug molecules
through small pores between the cells lining the gut wall (pore
absorption). Highly polar drugs with low molecular weight (less
than 200 Da) such as melibiose, water, and urea can pass cell
membranes through these small pores.
Melibiose
31 The Plasma-Time Curve
33 Physicochemical Properties
• Physicochemical properties: measurable characters by which
the chemical substance may interact with other systems.
• pKa; ionization of the drug: weak acids and bases, salt
formation
• Solubility: water solubility and lipid solubility
• Partition coefficient (lipophilicity/hydrophilicity)
• Stability: Chemical degradation, metabolism (oxidation,
reduction, hydrolysis, conjugation, CYP450)
34 Many Drugs are Weak Acids or Bases, Which Means They
Can Ionise
35 • Common acidic functional groups in drugs and their pKa values
O
R
4-5
10
OH
OH
10
<2
O
R
NH
R
O
8-10
36 • Common basic functional groups in drugs and their pKa values
R
10.0
NH2
R
NH
10.6-11.0
R
R
N
R
9.8-10.8
R
NH2
HN
N
6.5
5.2
N
4.6
37 • Drugs will encounter different pH values in different body
compartments
• The ratio of the ionized to the unionized forms of the drug will
differ from one compartment to another inside the body
pH values in different body
compartments
Plasma
7.35 – 7.45
Buccal cavity 6.2 – 7.2
Stomach
1.0 – 3.0
Duodenum 4.8 – 8.2
Jejunum & ileum
7.5 – 8.0
Colon
7.0 – 7.5
38 What determines the ratio of the ionized
to the unionized forms (degree of ionization) for a given
drug?
1- The dissociation constant, pKa (which is fixed for a given drug)
2- The pH of the solution which the drug is in (which is variable)
39 • pKa is a different term than pH
• pH is simply a measure of the [H+] concentration in a given soluti
You can’t tell from the pKa value whether the species in
question is acidic or basic
40 How can we predict the %ionization for acidic or basic drugs
OH
O
NH 2
O
HN
CH 3
NH
O
pKa of amobarbital = 8.0
pKa of phenylpropanolamine = 9.4
Predict their %ionization at pH 7.4
41 • Predict %ionization for the following drugs in intestine:
Cl
O
O
S
N
O
Cl
pKa = 6.0
N
O H
N
H
HN
pKa = 4.1
42 • Predict %ionization of phenylbutazone (acidic, pKa = 4.5) and
diazepam (basic, pKa = 3.4) at different pH values.
pH value
Acidic drug
(%ionization)
Basic drug
(%ionization)
2 (Stomach)
6 (small
intestine)
7.4 (blood)
0.32%
96.9%
96.2%
0.3%
99.9%
0.0%
43 What is the importance of studying the ionization of drugs?
• The unionized molecules will pass through biological
membranes
In general, the ionized molecules that did not pass through the
membrane will re-establish equilibrium and become a mixture of
ionized and unionized forms, so more unionized molecules can
pass.
Drug
Drug
unionized form
ionized form
Absorption Absorption
44 Acidic drug
Basic drug
45 O
-O
O
N
N+
OH
N
OH
5-Nitrosalicylic acid
pKa = 2.3
pH
N
O
Aminopyrine
pKa = 5.0
% Intestinal absorption
4
40
21
5
27
35
7
0
48
8
0
52
46 Ionization of drug: Summary
For acids:
• A high pka means the species is predominantly unionised
• A low pka means the species is predominantly ionised
47 For bases:
• A high pka means the species is predominantly ionised
• A low pka means the species is predominantly unionised
48 • In general, it is found that the most effective drugs (acidic or
basic) have a pKa value in the range 6.0-8.0. In other words,
they are partially ionized at blood pH and can easily equilibrate
between their ionized and non-ionized forms.
49 Why unionized form of the drug will be absorbed?
• Unionized form of drug is considered to be lipophilic (fat
soluble) so can pass through membrane
• Ionized form of the drug is water soluble (hydrophilic)
• The drug should have both lipid solubility and water solubility to
be absorbed and distributed to the site of action and there
should be a balance between the two properties.
O
O
OH
O
ibuprofen
H
H
H
NH2
NH3
H
H
H
HO
H
H
HO
H
OH
H
HO
H
O
HO
O
HO
OH
H
HO
O
H
H
H
O
N
O
NH
H
H
H
H
OH
O
OH
H
H
OH
O
OH
O
HO
HO
diphenhydramine
50 Physicochemical Properties Affecting Drug
Absorption/ Water Solubility vs. Lipid Solubility
• Drug should have a balance between water
(hydrophilicity) and lipid solubility (lipophilicity)
solubility
• The drug should have some water soluble:
1- Should be soluble in the gastric fluids
2- Blood which is the distribution vehicle
3- Water is the reaction medium of the biological systems
• The drug should have some lipid solubility:
To pass through the biomembranes (phospholipid bilayers)
• The measurement of the balance between hydrophilicity and
lipophilicity of drug is represented by the partition coefficient or
Log P value
51 Physicochemical Properties Affecting Drug
Absorption/ Partition Coefficient
• The ratio of drug concentration (unionized form) in the oil phase
to its concentration in the water phase at equilibrium
P = [Drug]oil / [Drug]aq
• Partition coefficient is measured experimentally
• Octanol is used to mimic the
amphiphilic nature of lipid,
because it has a polar head
group (primary alcohol) and a
long hydrocarbon chain.
• In some
by chloroform.
cases
52
octanol
is • It is more common to use Log P instead of P
• P = [Drug]oil/[Drug]aq = (0.01 M/ 1.0 M) = 0.01;
LogP = -2….hydrophilic
• P = [Drug]oil/[Drug]aq = (0.1 M/ 0.001 M) = 100;
LogP = 2….lipophilic
In general,
log P > 2: highly lipophilic
log P < 0: hydrophilic
53 Log P = -1.56
Log P = 2.39
54 Experimental log P values for drugs are in the literature
55 Physicochemical Properties Affecting Drug
Absorption/ Relation between Partition Coefficient
and Oral absorption
Barbiturate
Partition
Coefficient
LogP
%Absorbed
Barbital
0.7
-0.15
12
Aprobarbital
4.9
0.69
17
Butethal
11.7
1.07
24
Pentobarbital
28.0
1.45
30
Secobarbital
50.7
1.71
40
Hexethal
> 100
> 2.00
44
• Partition coefficient (Chloroform/water)
56 Barbiturate
R1
O
HN
R2
O
NH
O
R1
R2
-CH2CH3
-CH2CH3
(1.07) Butethal
-CH2CH3
-(CH2)3CH3
(1.45) Pentobarbital
-CH2CH3
-CH2(CH3)(CH2)2CH3
(-0.15) Barbital
(0.69) Aprobarbital
(1.71) Secobarbital
(2.00) Hexethal
-CH2(CH3)(CH2)2CH3
-CH2CH3
-(CH2)5CH3
• Compare the number of carbon atoms between the compounds
• Take in consideration the branching of the alkyl chain
• Take in consideration the presence of unsaturation (less hydrogen
atoms)
57 Physicochemical Properties Affecting Drug
Absorption/ Distribution Coefficient
• If a compound can ionise then the observed partitioning
between water and octanol will be pH dependent.
octanol phase
[un-ionised]octanol
insignificant
P
aqueous phase
[un-ionised]aq
For an acidic compound:
D=
[ionised]aq
H+aq + A-aq
[HA]octanol
-
[HA]aq + [A ]aq
For a basic compound:
D=
HAaq
Ka
BH+aq
[B]octanol
[BH+]aq + [B]aq
H+aq + Baq
Distribution coefficient D
(usually expressed as
logD) is the effective
lipophilicity
of
a
compound at a given
pH, and is a function of
both the lipophilicity of
the
un-ionised
compound
and
the
degree of ionisation.
58 Relationship between logD, logP and pH for an
acidic drug
O
logP=4.25
O
5
50% unionized
4
logD
N
10%
3
OH
O
1%
2
Cl
0.1%
1
Indomethacin
0.01%
0
0.001% unionized
-1
-2
2
3
4
5
6
7
8
9
10
pH
pKa=4.50
59 Cl
O
4
O
O
3
N
H
Cl
O
2
O
O
O
1
logD
O
N
H
NH2
H
N
NH3+
-1
N
N
H
N
-3
O
O
0
-2
Amlodipine
pKa=9.3
N
NH+
S
S
N
H
CN
N
H
Cimetidine
pKa=6.8
CN
N
H
N
H
-4
3
4
5
6
7
8
9
10
11
pH
60 OH
pKa2 = 9.8
pKa1 = 4.4
0.5
NH2
0
logD
-0.5
-1
O
OH
-1.5
-2
NH2
NH3+
-2.5
2
3
4
5
6
7
8
9
10
11
12
pH
61 Physicochemical Properties Affecting Drug
Absorption/ Water solubility
Why drug should have water solubility?
62 The more H-bonds possible - the more water soluble
H
H
O
O
H
H
Alchohol
R
O
H
3 H-Bonds
H
H
O
H
Primary amine
R
H
N H
O
3 H-Bonds
H
H
H
H
H
O
H
H
O
O
H
H
Aldehyde / ketone
2 H-Bonds
O
R
H
O
R'
Secondary amine
R'
R
O
O
H
H
H
3 H-Bonds
O
H
O
O
2 H-Bonds
H
R'
O
R
N H
H
H
Ester
H
Secondary amine
R
1 H-Bonds
N R''
R
H
O
H
O
H
63 64 • Giving the drug as salt can be used to enhance its water
solubility.
Can any salt increase drug hydrophilicity??
• The salt must be highly dissociable
• Highly dissociable salts are those formed from strong acids
with strong bases (e.g. NaCl), weak acids with strong bases
(e.g. Na Phenobarbital), or strong acids with weak bases (e.g.
atropine sulfate).
Remember:
Acid + base
salt + water
65 Phenobarbital
Sodium phenobarbital
Atropine sulfate
Example:
water
solubilities of different salt
forms of selective drugs
• In general, low molecular
weight salts are water
soluble and high molecular
weight salts are insoluble.
66 Physicochemical Properties Affecting Drug
Absorption/ Water solubility prediction
1. The empirical approach
Based on carbon-solubilizing potential of several organic
functional groups.
OH
HO
HO
H
N
In general:
• Structural features that increase
lipophilicity: Aromatic and aliphatic
hydrocarbons and Halogens
• Structural
features
that
reduce
lipophilicity:
- Polar: O, N
- Groups that ionize (e.g. carboxylates
and amines)
67 Water-solubilizing potential (SP) of organic functional groups
Functional Group
SP
Alcohol
3 to 4 carbons
Phenol
3 to 4 carbons
Ether
2 carbons
Aldehyde
2 carbons
Ketone
2 carbons
Amine
3 carbons
Carboxylic Acid
3 carbons
Ester
3 carbons
Amide
2 to 3 carbons
Urea, Carbonate,
Carbamate
2 carbons
• Note: each charge on a molecule (cationic or anionic)
contributes a solubilizing potential of 20 to 30 carbon atoms.
• Functional groups that can interact either through intramolecular
hydrogen or ion-ion interactions will decrease the solubilizing
potential of each group.
68 Example: predicting water solubility using the empirical
approach
3 carbons
3 carbons
3 carbons
Anilerdine
69 2. Analytical /quantitative approach (fragmental constants)
•It involves calculating an approximate logP
•Because each organic functional group contained within the
molecule contributes to the overall hydrophobic/hydrophilic nature
of the molecule, a hydrophobic/hydrophilic value (the hydrophobic
substituent constant π or f
• can be assigned to each organic functional group.
70 Exceptions
• When two substituents can hydrogen bond to each other, this
will reduce the interaction with water and raises log P.
• The effect of a complete shape is particularly noticeable when
comparing normal with branched alkyl groups as in n-butanol
and t-butanol.
71 Hydrophilic-lipophilic values (π) for organic fragments
Fragments
Π value
C (aliphatic)
+ 0.5
Phenyl
+ 2.0
Cl
+ 0.5
IMHB (intramolecular H-bond)
+ 0.65
S
0.0
O=C-O (carboxyl)
- 0.7
O=C-N (amide, imide)
- 0.7
O (hydroxyl, phenol, ether)
- 1.0
N (amine)
- 1.0
O2N (aliphatic)
- 0.85
O2N (aromatic)
- 0.28
72 Common lipophilic and hydrophilic groups:
Log P Fragment contribution
Fragment
Aliphatic
Aromatic
Fragment
Aliphatic
Aromatic
-F
-0.38
0.37
C6H4
1.67
1.67
-Cl
0.06
0.94
-H
0.23
0.23
-Br
0.20
1.09
-NH-
-2.15
-1.03
-I
0.59
1.35
-OH
-1.64
-0.44
-NO2
-1.16
-0.03
-NH2
-1.54
-1.00
-O-
-1.82
-0.61
-SH
-0.23
0.62
-S-
-0.79
0.03
-CONH-
-2.71
-1.81
-CH3
0.89
0.89
-COOH
-1.11
-0.03
-CH2-
0.66
0.66
-CONH2
-2.18
-1.26
-CH<
0.43
0.43
-CN
-1.27
-0.34
>C<
0.20
0.20
-CO-
-1.90
-1.09
C6H5
1.90
1.90
-CO2-
-1.49
-0.56
Heteroaromatic rings must be treated separately.
73 Example 1:
Fragment
Aliphatic
Aromatic
Fragment
Aliphatic
Aromatic
-F
-0.38
0.37
C6H4
1.67
1.67
-Cl
0.06
0.94
-H
0.23
0.23
-Br
0.20
1.09
-NH-
-2.15
-1.03
-I
0.59
1.35
-OH
-1.64
-0.44
-NO2
-1.16
-0.03
-NH2
-1.54
-1.00
Log P = 1.7
-O-
-1.82
-0.61
-SH
-0.23
0.62
-S-
-0.79
0.03
-CONH-
-2.71
-1.81
-CH3
0.89
0.89
-COOH
-1.11
-0.03
P = 10
P = 50.12
-CH2-
0.66
0.66
-CONH2
-2.18
-1.26
-CH<
0.43
0.43
-CN
-1.27
-0.34
P = [50.12]/[1]
>C<
0.20
0.20
-CO-
-1.90
-1.09
Lipophilic
C6H5
1.90
1.90
-CO2-
-1.49
-0.56
1.7
P = [Co]/[Cw]
74 Example 2:
Fragment
Aliphatic
Aromatic
Fragment
Aliphatic
Aromatic
-F
-0.38
0.37
C6H4
1.67
1.67
-Cl
0.06
0.94
-H
0.23
0.23
-Br
0.20
1.09
-NH-
-2.15
-1.03
-I
0.59
1.35
-OH
-1.64
-0.44
-NO2
-1.16
-0.03
-NH2
-1.54
-1.00
-O-
-1.82
-0.61
-SH
-0.23
0.62
-S-
-0.79
0.03
-CONH-
-2.71
-1.81
P = 10
-CH3
0.89
0.89
-COOH
-1.11
-0.03
P = 0.93
-CH2-
0.66
0.66
-CONH2
-2.18
-1.26
P = [Co]/[Cw]
-CH<
0.43
0.43
-CN
-1.27
-0.34
>C<
0.20
0.20
-CO-
-1.90
-1.09
C6H5
1.90
1.90
-CO2-
-1.49
-0.56
Log P = -0.03
-0.03
P = [0.93]/[1]
hydrophilic
75 Fragments
Π value
C (aliphatic)
+ 0.5
Phenyl
+ 2.0
Cl
+ 0.5
IMHB
(intramolecular Hbond)
+ 0.65
S
0.0
O=C-O (carboxyl)
- 0.7
O=C-N (amide,
imide)
- 0.7
O (hydroxyl,
phenol, ether)
- 1.0
N (amine)
- 1.0
O2N (aliphatic)
- 0.85
O2N (aromatic)
- 0.28
Fragment
Aliphatic
Aromatic
Fragment
Aliphatic
Aroma
tic
-F
-0.38
0.37
C6H4
1.67
1.67
-Cl
0.06
0.94
-H
0.23
0.23
-Br
0.20
1.09
-NH-
-2.15
-1.03
-I
0.59
1.35
-OH
-1.64
-0.44
-NO2
-1.16
-0.03
-NH2
-1.54
-1.00
-O-
-1.82
-0.61
-SH
-0.23
0.62
-S-
-0.79
0.03
-CONH-
-2.71
-1.81
-CH3
0.89
0.89
-COOH
-1.11
-0.03
-CH2-
0.66
0.66
-CONH2
-2.18
-1.26
-CH<
0.43
0.43
-CN
-1.27
-0.34
>C<
0.20
0.20
-CO-
-1.90
-1.09
C6H5
1.90
1.90
-CO2-
-1.49
76
-0.56 Fragments
Π value
C (aliphatic)
+ 0.5
Phenyl
+ 2.0
Cl
+ 0.5
IMHB (intramolecular Hbond)
+ 0.65
S
0.0
O=C-O (carboxyl)
- 0.7
O=C-N (amide, imide)
- 0.7
O (hydroxyl, phenol, ether)
- 1.0
N (amine)
- 1.0
O2N (aliphatic)
- 0.85
O2N (aromatic)
- 0.28
Fragments
π
2 amines
-2.0
9 aliphatic
carbons
+3.5
2 phenyl rings
+4.0
1 ester
-0.7
logP
+4.8
(lipophilic)
77 Drug Absorption/ Oral absorption/ Lipinski’s rule
of five
• Orally administered drugs that are absorbed from the gut tend
to obey what is known as Lipinski’s rule of five (because the
factors concerned involved numbers that are multiples of five).
Actually they are more like guidelines rather than rules:
•
•
•
•
A molecular weight less than 500
No more than 5 hydrogen bond donor (HBD) groups
No more than 10 hydrogen bond acceptor (HBA) groups
A calculated log P value less than +5 (log P is a measure of
a drug’s hydrophobicity)
78 H
O
O
H
O
H
H
O
H
O
H
H
N
O
H
N
O
H
H
H
H
H
O
H
O
O
H
O
H
O
N
O H
H
H
O
+
H
O
H
H
H
H O H
N
H
O
N
O
H
O
N
H
H
H
H
H
• De-solvation and formation of a neutral molecule is
unfavourable if the compound forms many hydrogen or ionic
bonds with water.
• So, as a good rule of thumb, you don ’ t want too many
hydrogen bond donors or acceptors, otherwise the drug won’t
get from the gut into the blood.
• There are some exceptions to this – sugars, for example, but
these have special transport mechanisms.
79 Veber has carried out further research to find guidelines
independent of molecular weight. His findings demonstrated that
molecular flexibility is an important factor in oral bioavailability.
Also he used the polar surface area of the molecule as a factor
instead of the number of hydrogen bonding groups.
• A polar surface area ≤ 140 Å2 and ≤ 10 rotatable bonds, or
• ≤ 12 hydrogen bond donors and acceptors in total and ≤ 10
rotatable bonds
80 Paracetamol…..polar surface area indicated by red
HO
NH
O
81 • A rotatable bond is defined as any single non-ring bond,
attached to a non-terminal, non-hydrogen atom. Amide C-N
bonds are not counted because of their high barrier to rotation.
OH
O
O
H2N
OH
O
H
N
No. of rotatable
bonds
H
N
Bioavailability
Atenolol
8
50%
Propranolol
6
90%
82 Example:
Which of the following compounds obeys Lipinski’s rule of five and
which doesn’t?
Cephalexin
Ceftriaxone
Drug
Diazepam
pKa
logP
MWt
HBD
HBA
Rot. bonds
Ceftriaxone
3.96
-1.7
554
5
15
8
Cephalexin
4.5
0
347.1
4
7
4
Diazepam
3.4
2.9
284.1
0
3
1
83 Drug Distribution
• The reversible transfer of a drug to and from the systemic
circulation
Drug
Absorption
Distribution Tissues
Blood
• Compounds can distribute out of plasma into tissues:
• Main factors influencing distribution are pKa, lipophilicity,
plasma protein binding
(only unbound tissue is free to distribute).
• Tissue pH is slightly lower than plasma pH
Basic compounds tend to distribute out of plasma into tissue more
than acids.
84 At pH = 5.0, the ratio of the protonated to unprotonated forms of
morphine (weak base with an ionizable amino group, pKa = 7.0)
would be
A.
B.
C.
D.
E.
1:100
1:10
1:1
10:1
100:1
85 Predict the ionized form of ciprofloxacin in stomach (pH = 2.0)
and in intestine (pH =7.0).
O
O
F
HO
N
N
NH
pKa (COOH) = 5.8
pKa (amine) = 8.7
86 • Loratadine is an orally available drug, it has a pKa of 5.0, answer the
followings according to its structure:
• Is it basic, acidic or neutral compound?
• Calculate the % ionization:
• In stomach (pH = 2):
• In intestine (pH = 8):
• Based on your calculation, from where do you think loratadine
will be absorbed?
87 Determine the hydrogen bond donors and hydrogen bond
acceptors
88 Predict the water solubility of serotonin using:
H
N
HO
NH 2
serotonin
A- Empirical approach
B- Analytical approach
Fragments
Π value
C (aliphatic)
+ 0.5
Phenyl
+ 2.0
Cl
+ 0.5
IMHB (intramolecular Hbond)
+ 0.65
S
0.0
O=C-O (carboxyl)
- 0.7
O=C-N (amide, imide)
- 0.7
O (hydroxyl, phenol, ether)
- 1.0
N (amine)
- 1.0
O2N (aliphatic)
- 0.85
O2N (aromatic)
89
89 Predict the water solubility of the following drug using the
empirical approach:
CH 3
N
H 3C
O
NH
Functional Group
SP
Alcohol
3 to 4 carbons
Phenol
3 to 4 carbons
Ether
2 carbons
Aldehyde
2 carbons
Ketone
2 carbons
Amine
3 carbons
Carboxylic Acid
3 carbons
Ester
3 carbons
Amide
2 to 3 carbons
Urea, Carbonate,
Carbamate
2 carbons
90 Calculate the water solubilizing potential of the following drugs
using the empirical approach:
O
OH
O
H
N
H
Functional Group
SP
Alcohol
3 to 4 carbons
Phenol
3 to 4 carbons
Ether
2 carbons
Aldehyde
2 carbons
Ketone
2 carbons
Amine
3 carbons
Carboxylic Acid
3 carbons
Ester
3 carbons
Amide
2 to 3 carbons
Urea, Carbonate,
Carbamate
2 carbons
91 Which of the following is expected to have the lowest logD and the
highest logD values?
R1
O
O
N
R2
N
O
X
A
R1
N
R2
Ar
B
OH
HN
S
N
C
OH
HN
D
OH
HN
OH
F
HN
OH
O
X
Ar
N
N
N
92 Which of the following drugs is expected to be absorbed orally
according to Lipinski’s rule,?
H3C N
CH3
OH
OH
C
CCH3
HO
HO
O
O
O
ClogP = 4.74, Mwt = 429 g/mol
ClogP = 1.09, Mwt = 328.2 g/mol
OH
ClogP = 6.7, Mwt = 272.2 g/mol
CLogP is more than +5
93 How many rotatable bonds in each of the following drugs?
H 2N
OH
N
O N
N
N
O
OH
O
NH
O
O
S
O
Cl
NH 2
O
H
N
H 2N
NH
N
NH
NH
N
N
O
S
O
94
Introduction to Medicinal Chemistry
of 92
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