Medicinal

Chemistry
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
bladder
 survive a range of pHs
(1.5 to 8.0)
kidneys BBB  survive intestinal bacteria
 cross membranes
 survive liver metabolism
 avoid active transport to
bile
bile
duct
 avoid rapid excretion by
kidneys
 partition into target organ
liver
 avoid partition into
undesired places (e.g.
brain, foetus)
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).

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
O O
O O
 Binding of a compound
OH O
at its site of action
-
- -
O O
 E.g.

 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 7.2 ionised to different extents in
humour different parts of the body.
Blood 7.4
Colon 5-8 This means that, for example,
basic compounds will not be so
Duodenum 4.4-6.6
well absorbed in the stomach
(fasting)
than acidic compounds because
Duodenum (fed) 5.2-6.2
it is generally the unionised form
Saliva 6.4 of the drug which diffuses into
Small intestine 6.5 the blood stream.
Stomach 1.4-2.1
(fasting)
Stomach (fed) 3-7
Sweat 5.4
Urine 5.5-7.0 5
 Ionisation constants
Acids include
 For an Ka strong acids,
+
acid: 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

2.5

2
2 3 4 5 6 7 8 9 10 11

pKa
O O O O
S R2 S R2
R1 N R1 N
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
Name (pKa)
groups
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 N
-
R R N R
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
Guanidine NH
NH2
NH
(12-13) NH2 NH2

12
 Effects of substituents on ionisation
 Substituents have similar effects on the ionisation of different series of
compounds.

N  Trends such as this are

5
found for a very wide
X range of aromatic
Basicity decreases

log(KX/KH) pyridines

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

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

 Enzyme / receptor binding  Toxicity

14
 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
15
 Groups increase/decrease p-value
Group p value Group p value
O=C-N -0.7
C +0.5
(amide)
(aliphatic)
O -1.0
Phenyl +2.0
(hydroxyl, phenol)
Cl +0.5
N -1.0
O2NO nitrate ester +0.2
(amine)

Intramolecular H-bond +0.65

Aliphatic NO2 -0.85
S 0.0

O=C-O -0.7 Aromatic NO2 -0.28

(carboxyl)

16
 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 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

17
 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

logP 1.7 2.0 1.2 2.9 2.2 3.2

18
 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

logP 1.7 2.0 1.2 2.9 2.2 3.2

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?

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

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

pKa1 = 4.4 pKa2 = 9.8

0.5
NH2
0

-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

A H OH2 + B HOH A H B + HOH OH2

 Intramolecular hydrogen bonds are more readily formed in water

O O O
+ +
O H -H O -H O
 maleic (cis) O - H
O
pKa1=1.91 O pKa2=6.33
OH O O

HO2C + HO2C + CO2-

-H -H

 fumaric (trans) CO2H pKa1=3.03 CO2- pKa2=4.54 CO2-

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 O
H
O
H formation of a neutral molecule
H
H

 Exceptions to this – sugars, for example, but these have special transport
mechanisms.

27
 V. 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

28
 25
Molecular weight
20

15
Plot of frequency of
frequency %

occurrence against molecular

weight for 594 marketed oral
10
drugs

Molecular Weight

Most oral drugs have molecular weight < 500

29
 VI. 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
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

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

70
60
50
Percentage
40
of com- MW 0-499
pounds with 30 MW 500+
F >20% 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

 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)

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

 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.
34
Linking Physicochemical prop with drugs PK
Biological process in drug Physical chemistry
action model

Dissolution of drug in Solubility in buffer,

gastrointestinal fluids acid or base

logP, acid or base

Absorption from small , polar surface area,
intestine hydrogen bond counts,
M.Wt

Blood protein
logP and acid or base
Binding e.g. albumin

Distribution of compound
logP, acid or base
in tissues

35