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Physical Properties and

Drug Design

Lectures 13
Overview
 Introduction

 Ionisation
 Lipophilicity
 Hydrogen bonding

 Molecular size
 Rotatable bonds

 Bulk physical properties


 Lipinski Rule of Five

 The Drug Design Summary


What must a drug do other than bind?
An “ideal” oral drug must be able to:

 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.

 However, many complicated biological processes can be


modelled using simple physical chemistry models or
properties – and understanding these often drives both
the lead optimisation and lead identification phases of a
drug discovery program forward.

 This lecture will focus on oral therapy, but remember that


there are lots of other methods of administration e.g.
intravenous, inhalation, topical. These will have some of
the same, and some different, hurdles.
Reducing the complexity
Biological process in Underlying physical Physical chemistry
drug action chemistry model

Energy of dissolution;
Dissolution of drug in Solubility in buffer,
lipophilicity & crystal
gastrointestinal fluids acid or base
packing

logP, logD, polar


Absorption from small Diffusion rate, membrane
surface area, hydrogen
intestine partition coefficient
bond counts, MWt

Blood protein Binding affinity to blood Plasma protein binding,


binding proteins e.g. albumin logP and logD

Distribution of Binding affinity to cellular


logP, acid or base
compound in tissues membranes

https://www.youtube.com/watch?v=LnYVQkjVcJQ
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).

The acidity or basicity of a compound plays a major role in controlling:

 Absorption and transport to site of action


• Solubility, bioavailability, absorption and cell penetration, plasma
binding, volume of distribution
 Binding of a compound at its site of action
• un-ionised form involved in hydrogen bonding
• ionised form influences strength of salt bridges or H-bonds
 Elimination of compound
• Biliary and renal excretion
• CYP P450 metabolism
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
Duodenum (fasting) 4.4-6.6 • This means that, for example,
basic compounds will not be so
Duodenum (fed) 5.2-6.2
well absorbed in the stomach
Saliva 6.4
than acidic compounds since it
Small intestine 6.5 is generally the unionised form
Stomach (fasting) 1.4-2.1 of the drug which diffuses into
Stomach (fed) 3-7 the blood stream.
Sweat 5.4
Urine 5.5-7.0
Ionisation constants
 The equilibrium between un-ionised and ionised forms
is defined by the acidity constant Ka or pKa = -log10 Ka
 For an Ka +
acid: HA H + A

[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)

When an acid or base is 50% ionised:


pH = pKa
Ionisation of an acid – 2,4-dinitrophenol

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

Sulfonamide are synthetic antimicrobial agents that


contain the sulfonamide group.

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

H  This allows prediction of


0
-0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 the pKa of molecules
3-Me log(KX/KH) benzoic acids O OH before they are even
-1
4-Me made!

X
Lipophilicity

Lipophilicity (‘fat-liking’) is the most important physical property of a drug


in relation to its absorption, distribution, potency, and elimination.

Lipophilicity is often an important factor in all of the following, which


include both biological and physicochemical properties:

 Solubility  Biliary and renal clearance


 Absorption  CNS penetration
 Plasma protein binding  Storage in tissues
 Metabolic clearance  Bioavailability
 Volume of distribution  Toxicity
 Enzyme / receptor binding
Thermodynamics
• a system:
Some portion of the universe that you wish to
study

 The surroundings:
The adjacent part of the universe outside the
system

Changes in a system are associated with the transfer of


energy

Natural systems tend toward states of minimum energy


Energy States

Figure 5.1. Stability states. Winter (2001) An Introduction to


Igneous and Metamorphic Petrology. Prentice Hall.
Gibbs free energy is a measure of
chemical energy

All chemical systems tend naturally toward states


of minimum Gibbs free energy

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

 This is entropy driven (remember δG = δH – TδS). Hydrophobic


molecules are encouraged to associate with each other in water.
 Placing a non-polar surface into water disturbs network of water-water
hydrogen bonds. This causes a reorientation of the network of hydrogen
bonds to give fewer, but stronger, water-water H-bonds close to the non-
polar surface.
 Water molecules close to a non-polar surface consequently exhibit
much greater orientational ordering and hence lower entropy than bulk
water.
The hydrophobic effect
This principle also applies to the physical properties of drug molecules.

If a compound is too lipophilic, it may


 be insoluble in aqueous media (e.g. gastrointestinal fluid or blood)

 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

Conversely, if the compound is too polar, it may not be absorbed through


the gut wall due to lack of membrane solubility.

So it is important that the lipophilicity of a potential drug molecule is correct.

How can we measure this?


Partition coefficients
P
Xaqueous Xoctanol

Partition coefficient P (usually expressed as log10P or logP) is defined as:

[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.

1-Octanol is the most frequently used lipid phase in pharmaceutical


research. This is because:

 It has a polar and non polar region (like a membrane phospholipid)


 Po/w is fairly easy to measure
 Po/w often correlates well with many biological properties
 It can be predicted fairly accurately using computational models
Calculation of logP
LogP for a molecule can be calculated from a sum of fragmental
or atom-based terms plus various corrections.
logP = S fragments + S corrections
H
C H
Branch H C C clogP for windows output
O
C H C: 3.16 M: 3.16 PHENYLBUTAZONE
H C
H C C Class | Type | Log(P) Contribution Description Value
N
H C C H H
H N FRAGMENT | # 1 | 3,5-pyrazolidinedione -3.240
C H C C
H C H C H
ISOLATING |CARBON| 5 Aliphatic isolating carbon(s) 0.975
H C H
C ISOLATING |CARBON| 12 Aromatic isolating carbon(s) 1.560
O
C EXFRAGMENT|BRANCH| 1 chain and 0 cluster branch(es) -0.130
H H C
C EXFRAGMENT|HYDROG| 20 H(s) on isolating carbons 4.540
H
Phenylbutazone H
EXFRAGMENT|BONDS | 3 chain and 2 alicyclic (net) -0.540

RESULT | 2.11 |All fragments measured clogP 3.165


Blood clot preventing activity
of salicylic acids
O OH
9
OH

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?

Binding to Aqueous Binding to Absorption Binding to Binding to


logP enzyme / solubility P450 through blood / tissue hERG heart
receptor metabolising membrane proteins – ion channel -
enzymes less drug free cardiotoxicity
to act risk

So log P needs to be optimised


Distribution coefficients
If a compound can ionise then the observed partitioning between water and
octanol will be pH dependent.

[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.

It works by inhibiting the production of prostaglandins,


molecules known to cause these symptoms. It is marketed
under more than seventy different trade names.

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

For singly ionising bases in general:


logD = logP - log[1 + 10(pKa-pH)]
pH - Distribution behaviour of amphoteric
compounds
OH

pKa1 = 4.4 pKa2 = 9.8


0.5
NH2
0

-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

e.g. Monocarboxylate transporter 1 blockers N


R2

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

logD 1.7 2.0 1.2 2.9 2.2 3.2


How can lipophilicity be altered?
R1
O
O N

e.g. Monocarboxylate transporter 1 blockers N


R2

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

logD 1.7 2.0 1.2 2.9 2.2 3.2


Hydrogen bonding
 Intermolecular hydrogen bonds are virtually non-existent between small
molecules in water. To form a hydrogen bond between a donor and
acceptor group, both the donor and the acceptor must first break their
hydrogen bonds to surrounding water molecules
A H OH2 + B HOH A H B + HOH OH2

 The position of this equilibrium depends on the relative energies of the


species on either side, and not just the energy of the donor-acceptor
complex
 Intramolecular hydrogen bonds are more readily formed in water - they are
entropically more favourable.
O O O
+ +
O H -H O -H O
O - H
O
pKa1=1.91 O pKa2=6.33
OH O O

HO2C + HO2C + CO2-


-H -H

CO2H pKa1=3.03 CO2- pKa2=4.54 CO2-


Hydrogen bonding and bioavailability
Remember! Most oral drugs are absorbed through the gut wall by
transcellular absorption.
H
H
H O O
O H
H H O
O H 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 O O
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.
Molecular size
• Molecular size is one of the most important factors
affecting biological activity, but it’s also one of the most
difficult to measure.

• There are various ways of investigating the molecular size,


including measurement of:

 Molecular weight (most important)


 Electron density
 Polar surface area
 Van der Waals surface
 Molar refractivity
25 Molecular weight

20

15
Plot of frequency of
frequency %

occurrence against molecular


weight for 594 marketed oral
10 drugs

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

Most oral drugs have molecular weight < 500


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
OH
O
H
N bonds
O
Atenolol
H2N

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%

The number of rotatable bonds influences, in particular,


bioavailability and binding potency.

Why should this be so?


Number of rotatable bonds
Remember δG = δH – TδS ! A molecule will have to adopt a fixed
conformation to bind, and to pass through a membrane. This involves a
loss in entropy, so if the molecule is more rigid to start with, less entropy
is lost. But beware!
H H H H H H
R R H H R

H H H R R H

Any, or none, of these could be the active conformation!

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

When a compound is nearing nomination for entry


to clinical trials, we need to look at:
 Solubility, including in human intestinal fluid
 Hygroscopicity, i.e. how readily a compound
absorbs water from the atmosphere
 Crystalline forms – may have different properties
 Chemical stability (not a physical property! Look
at stability to pH, temperature, water, air, etc)

How can these be altered?

 Different counter ion or salt


 Different method of crystallisation
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

 molecular weight < 500


 logP < 5
 < 5 H-bond donors (sum of NH and OH)
 < 10 H-bond acceptors (sum of N and O)

An additional rule was proposed by Veber

 < 10 rotatable bonds

Otherwise absorption and bioavailability are likely to


be poor. NB This is for oral drugs only.
The Drug Design Summary
• In summary, while pharmacokinetic properties improve by modulating bulk
properties, potency also depends on these – particularly lipophilicity.
• There are then three approaches that could be adopted.

Potency
New receptor interaction
to increase potency and modulate
bulk properties

Find a substitution position not affecting


potency where bulk properties can be
modulated for good DMPK

Trade potency for


DMPK improvements
dose to man focus

logD/Clearance/CYP inhibition
Overview
 Introduction

 Ionisation
 Lipophilicity
 Hydrogen bonding

 Molecular size
 Rotatable bonds

 Bulk physical properties


 Lipinski Rule of Five

 The Drug Design Summary

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