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PhysicoChem Lec 1 2
PhysicoChem Lec 1 2
Lectures note 1:
Physico-Chemical Properties
1
Overview
Introduction
Ionisation
Lipophilicity
Hydrogen bonding
Molecular size Two lectures
Rotatable bonds
Bulk physical properties
Lipinski’s Rule of Five
2
What must a drug do other than bind?
An Oral drug must be able to:
dissolve
survive a range of pHs (1.5 to
bladder
8.0)
survive intestinal bacteria
kidneys BBB cross membranes
survive liver metabolism
avoid active transport to bile
avoid rapid excretion by kidneys
bile
duct partition into target organ
avoid partition into undesired
places (e.g. brain, foetus)
liver
3
I. Ionisation
Ionisation = protonation or deprotonation resulting in charged
molecules
About 85% of marketed drugs contain functional groups that are
ionised to some extent at physiological pH (pH 1.5 – 8).
-
OH O - -
O O
Elimination of compound
Biliary and renal excretion
CYP P450 metabolism
4
How does pH vary in the body?
Fluid pH So the same compound will be
Aqueous humour 7.2 ionised to different extents in
Blood 7.4 different parts of the body.
Colon 5-8
This means that, for example,
Duodenum (fasting) 4.4-6.6
basic compounds will not be so
Duodenum (fed) 5.2-6.2 well absorbed in the stomach
Saliva 6.4 than acidic compounds because
Small intestine 6.5 it is generally the unionised form
Stomach (fasting) 1.4-2.1 of the drug which diffuses into
the blood stream.
Stomach (fed) 3-7
Sweat 5.4
Urine 5.5-7.0
5
Ionisation constants
Acids include
For an acid: Ka strong acids,
+
HA H + A which
completely
The concentration ratio of both sides is constant given fixed dissociate in
analytical conditions and is referred to as the acid dissociation water, and weak
constant (Ka). acids, which only
[H+][A-] partially
Ka = dissociate. When
[AH]
an acid
For a base: dissociates, it
Ka releases a proton
BH+
+
H + B to make the
solution acidic,
[H+][B]
Ka = but weak acids
[BH+] have both a
dissociated state
When an acid or base is 50% ionised: (A-) and
undissociated
pH = pKa state (AH) that
coexist.
6
Ionisation of an acid – 2,4-dinitrophenol
OH O
100 NO2 NO2
-H+
90
80
70
NO2 NO2
60
pKa = 4.1
percent
% neutral
50
% anion
40
30
20
10
0
3 4 5 6 7 8 9 10 11
pH
7
Ionisation of an base – 4-aminopyridine
NH2 NH2
100
-H+
90
+
80
N N
70
H
60
pKa = 9.1
percent
% neutral
50
% cation
40
30
20
10
0
3 4 5 6 7 8 9 10 11
pH
8
Effect of ionisation on antibacterial potency of
sulphonamides
6.5 Ionised is the active
6 molecule.
Non-ionised is the
5.5
one can cross cell
5 membrane
potency
4.5
4
3.5
3
2.5
2
2 3 4 5 6 7 8 9 10 11
pKa
O O O O
S R2 S R2
R1 N N
R1
H
-
9
Examples of ionisable acidic groups
Name (pKa) Neutral form Conjugate base
-
OH O
Phenol
(9-11) R R
O O
Alkylcarboxylic R R
-
acid (5-6) OH O
O O
-
OH O
Arylcarboxylic
acid (4-5) R R
O O O O
Sulfonic acid R S R S
-
(0-1) OH O
O O O O
sulfonamide R S R S
(9-10) NH
-
NH2
10
Examples of ionisable acidic groups
Name (pKa) Neutral form Conjugate base
O
NH O
-O
N-arylsulfonamide S
NH O
S
(6-7) R R
R R
-
imide O O O O O O
(5-6) R NH R
R N
-
R R N R
-
Alkylthiol R SH R S
(10-11)
-
SH S
Thiophenol
(9-10) R R
11
Examples of ionisable basic groups
Name (pKa) Neutral form Conjugate base
NH2 +
NH3
Arylamine (~4)
R R
+
N NH
Aromatic amine
R R
(5-6)
R R
Imine (3-4) NH
+
NH2
+
1° Alkylamine R NH2 R NH3
(9-10) NH2
+
NH
2° Alkylamine
(10-11) R
R
NH +
NH2
Amidine R
R
NH2
(10-11) NH2
NH +
R R NH2
Guanidine NH NH
(12-13) NH2 NH2
12
Effects of substituents on ionisation
Substituents have similar effects on the ionisation of different series of
compounds.
4 3-CN 3-NO2
ionising functionalities.
This allows prediction of
3
the pKa of molecules
3-F before they are even
2 3-Cl
made!
1
4-F 4-Cl
0
H
-0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8
log(KX/KH) benzoic acids O OH
3-Me
-1
4-Me
Acidity increases
X
13
II. Lipophilicity
14
Partition coefficients
P
Xaqueous Xoctanol
[X]octanol
P=
[X]aqueous
P is a measure of the relative affinity of a molecule for the lipid and aqueous
phases in the absence of ionisation.
16
Calculation of logP
LogP for a molecule can be calculated from a sum of fragmental or atom-
based terms plus various corrections.
17
How can lipophilicity be altered?
R1
O
O N
O N S Ar
OH OH OH OH OH OH
R1
N N N N N N N
R2 O O
OH
F
O CF3
X
Ar
N N N N
18
How can lipophilicity be altered?
R1
O
O N
O N S Ar
OH OH OH OH OH OH
R1
N N N N N N N
R2 O O
OH
F
O CF3
X
Ar
N N N N
19
Blood clot preventing activity
of salicylic acids
9 O OH
OH
8.5
8 R1 R2
pIC50
7.5
O OH
7
O
6.5
2 3 4 5 6 O
logP Aspirin
20
What else does logP affect?
21
Relationship between logD, logP and pH for
an acidic drug O
logP=4.25 O
5 OH
4 50% neutral
N
10%
3 O
1%
2
logD
0.1% Cl
1
Indomethacin
0.01%
0
0.001% neutral
-1
-2
2 3 4 5 6 7 8 9 10
pH
For singly ionising acids in general:
pKa=4.50
logD = logP - log[1 + 10(pH-pKa)]
23
pH - Distribution behaviour of bases
Cl O
O
4
O O
3 N
H
Amlodipine
O
Cl
O
O pKa=9.3
2
O O NH2
N
1 H
O
logD
H CN
0 NH3+ N N
S
-1 N N N
H H
-2 H CN Cimetidine
N N
pKa=6.8
-3 S
NH+ N N
H H
-4
3 4 5 6 7 8 9 10 11
pH
For singly ionising bases in general:
logD = logP - log[1 + 10(pKa-pH)]
24
pH - Distribution behaviour of amphoteric
compounds
OH
-0.5
O
logD
-1
OH
-1.5
-2 NH2
NH3+
-2.5
2 3 4 5 6 7 8 9 10 11 12
pH
25
IV. Hydrogen bonding
Hydrogen bonding is the attractive force between a hydrogen atom covalently
bound to an electronegative atom (the donor) and a second electronegative atom
(the acceptor).
Intermolecular
O O O
+ +
O H -H O -H O
maleic (cis) O - H
O
pKa1=1.91 O pKa2=6.33
OH O O
26
Hydrogen bonding and bioavailability
Remember! Most oral drugs are absorbed through the gut wall by
transcellular absorption.
H
H
H O O
O H
O
H
H O H De-solvation O
O
H O H H N H
N H O
O H H
O H + H H N N
H N N
O
O H H O H O H
O H H
H H H H
O
H
O
H
O
H formation of a neutral molecule
H
Exceptions to this – sugars, for example, but these have special transport
mechanisms.
27
V. Molecular size
Electron density
28
25
Molecular weight
20
15
Plot of frequency of
frequency %
Molecular Weight
OH
No. of rotatable
O
H
N bonds
O
Atenolol
H2N
OH
H
O N
Propranolol
30
Number of rotatable bonds
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
No. of rotatable Bioavailability
O
H
N bonds
O
Atenolol 8 50%
H2N
OH
H
O N
Propranolol 6 90%
*The number of rotatable bonds influences, in particular, bioavailability and binding potency.
Why should this be so?
31
Number of rotatable bonds
Remember: A molecule will have to adopt a fixed conformation to bind,
and to pass through a membrane. BUT, if you make if rigid!!
H H H H H H
R R H H R
H H H R R H
70
60
50
Percentage of
compounds 40 MW 0-499
with F >20% 30 MW 500+
20
10
0
# Rot 0-7 # Rot 8-10 # Rot 11+
32
Bulk physical properties
When a compound is nearing nomination for entry
to clinical trials, we need to look at:
Solubility, including in human intestinal fluid
33
This seems like a lot to remember!
There are various guidelines to help, the most well-
known of which is the Lipinski Rule of Five
Blood protein
logP and acid or base
Binding e.g. albumin
Distribution of compound in
logP, acid or base
tissues
35