Fundamentals of Medicinal Chemistry

NH

HN N

Histamine

N N

H

NH 2

C

HN N

H

H NH

2

H

H

H

Steric hindrance

between the H

atoms

Conformational

restriction by the

use of a ring

HO NH 2

HO

HO

HO

Dopamine

NH 2

Conformational

restriction by the

use of a ring

*

**

(a) (b)

Figure 3.4 Examples of the use of conformational restrictions to produce analogues of (a)

histamine and (b) dopamine. Bonds marked * can exhibit free rotation and form numerous

conformers

As well as an effect on the activity, different stereoisomers will also exhibit

differences in other physiochemical properties, such as absorption, metabolism

and elimination. For example, ()norgestrel is absorbed at twice the rate

of (þ)norgestrel through buccal and vaginal membranes. The plasma half

life of S-indacrinone is 2–5 hours whilst the value for the R isomer is 10–12

hours.

H

H

H

H

O

OH

CH 3

CH CH

H

H

H

H

O

OH

CH 3

CH CH

(−) Norgestrel

Ph

CH 3

O

HOOCCH 2 O

HOOCCH 2 O

Cl

Cl

Cl

Cl

S-Indacrinone

(+) Norgestrel Ph

CH 3

O

R-Indacrinone

3.3 Solubility and drug design

The relative solubilities of drugs in the aqueous media and lipid tissues of the

body play a major part in their absorption and transport to their sites of action.

SOLUBILITY AND DRUG DESIGN 61