Professional Documents
Culture Documents
Drug Design
Lectures 13
Overview
Introduction
Ionisation
Lipophilicity
Hydrogen bonding
Molecular size
Rotatable bonds
dissolve
survive a range of pHs (1.5
bladder to 8.0)
survive intestinal bacteria
kidneys BBB
cross membranes
survive liver metabolism
avoid active transport to bile
bile avoid excretion by kidneys
duct
partition into target organ
avoid partition into
liver undesired places (e.g. brain)
Why are physical properties
important in medicinal chemistry?
So, before the drug reaches its active site, there are
many hurdles to overcome.
Energy of dissolution;
Dissolution of drug in Solubility in buffer,
lipophilicity & crystal
gastrointestinal fluids acid or base
packing
https://www.youtube.com/watch?v=LnYVQkjVcJQ
Ionisation
Ionisation = protonation or deprotonation resulting in charged
molecules
[H+][A-] 100
Ka = % ionised =
[AH] 1 + 10(pKa - pH)
For a
Ka +
base: BH+ H + B
[H+][B] 100
Ka = % ionised =
[BH+] 1 + 10(pH - pKa)
100
OH O
90
NO2 NO2
80 -H+
70
60
percent
% neutral
50 NO2 NO2
% anion
40
30 pKa = 4.1
20
10
0
3 4 5 6 7 8 9 10 11
pH
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
Sulfonamide
O O O O
S R2 S R2
R1 N N
R1
H
-
Effect of ionisation on antibacterial potency
of sulphonamides
6.5
6
From pH 11 to 7
5.5 potency increases
5 since active species
is the anion.
potency
4.5
4
From pH 7 to 3
3.5 potency decreases
3 since only the neutral
form of the
2.5
compound can
2 transport into the cell.
2 3 4 5 6 7 8 9 10 11
O O pKa
O O
S R2 S R2
R1 N N
R1
H
-
Effects of substituents on ionisation
Substituents have similar effects on the ionisation of different series of
compounds.
This is an example of a
5 linear free energy
relationship.
log(KX/KH) pyridines
4 3-CN 3-NO2
N
3 Trends such as this are
found for a very wide
X 3-F
2 3-Cl range of aromatic ionising
functionalities.
1 4-F 4-Cl
X
Lipophilicity
The surroundings:
The adjacent part of the universe outside the
system
G = H - TS
Where:
G = Gibbs Free Energy
H = Enthalpy (heat content)
T = Temperature in Kelvins
S = Entropy (can think of as randomness)
The hydrophobic effect
Molecular interactions – why don’t oil and water mix?
H
H O O H H
H H H
H O H H
H O H O O H H
H H H H
H H
H
O O O H O H H
H H
H H H H H
O O
H O H
H H H H H H
O
bind too strongly to plasma proteins and therefore the free blood
concentration will be too low to produce the desired effect
distribute into lipid bilayers and be unable to reach the inside of the cell
[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.
8.5
R1 R2
8
pIC50
7.5 O OH
7 O
O
6.5
2 3 4 5 6 Aspirin
logP
What else does logP affect?
[un-ionised]octanol insignificant
octanol phase
P
Distribution coefficient
D (usually expressed
aqueous phase Ka as logD) is the
[un-ionised]aq [ionised]aq
effective lipophilicity of
a compound at a given
For an acidic compound: HAaq H+aq+ A-aq pH, and is a function of
both the lipophilicity of
[HA]octanol the un-ionised
D=
[HA]aq + [A-]aq compound and the
degree of ionisation.
For a basic compound: BH+aq H+aq+ Baq
[B]octanol
D=
[BH+]aq + [B]aq
Indometacin (INN) is a non-steroidal anti-inflammatory
drug (NSAID) commonly used as a prescription medication
to reduce fever, pain, stiffness, and swelling.
O
OH
Cl
Indomethacin
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)]
pH - Distribution behaviour of bases
Cl O
O
4
O O
3 N Amlodipine
H
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
-0.5
logD
-1 O
OH
-1.5
-2 NH2
NH3+
-2.5
2 3 4 5 6 7 8 9 10 11 12
pH
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
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
20
15
Plot of frequency of
frequency %
0
0
00
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
10
0-
0-
0-
0-
0-
0-
0-
0-
0-
0-
0-
0-
0-
0-
0-
0-
0-
0-
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
Molecular Weight
OH
H
O N
Propranolol
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.
No. of rotatable Bioavailability
OH
O
H
N bonds
O
Atenolol 8 50%
H2N
OH
H
O N
Propranolol 6 90%
H H H R R H
70
60
50
Percentage of 40
compounds MW 0-499
with F >20% 30 MW 500+
20
10
0
# Rot 0-7 # Rot 8-10 # Rot 11+
Bulk physical properties
Potency
New receptor interaction
to increase potency and modulate
bulk properties
logD/Clearance/CYP inhibition
Overview
Introduction
Ionisation
Lipophilicity
Hydrogen bonding
Molecular size
Rotatable bonds