Fundamentals of Medicinal Chemistry

Table 4.1 Examples of the ways in which the size and shape of the carbon skeletons of lead

compounds may be changed to produce new analogues

Change Notes Example, the lead compound is given in

square brackets([ ])

The number

of methylene

(CH 2 ) groups

in a chain or

ring.

Increasing the number

of CH 2 groups in a

chaincan lead to micelle

formation which can

reduce drug activity

(Fig. 4.1). Changing

NCl

S

CH 2 CH 2 CH 2 N(CH 3 ) 2

N Cl

CH 2 CH 2 CH 2 N(CH 3 ) 2

the number of CH 2

groups in aringmay

lead to a change in

activity.

Chlorpromazine

(Antipsychotic)

Clomipramine

(Antidepressant)

The degree of

unsaturation.

Introduction of a double

bond increases the rigidity

of the structure and in

some cases the possibility

of E and Z isomers. The

reduction of double bonds

makes the structure more

OH

O

CH 2 OH

HO

O

C

OH

O

CH 2 OH

HO

O

C

flexible. Cortisol

(Anti-inflammatory)

Prednisone (Potency

30)Note.NoE

isomer is possible in

this example.

Addition or

removal of a

ring.

Introduction of a ring

may result in the filling

of a hydrophobic pocket

in the target, which

might improve the

binding of the drug to

its target.

O

CH 3 O O

N

H

CH 3 O

O

CH 3 O

N

H

3-(3,4-Dimethoxy

phenyl)-butyrolactam

(Antidepressant)

Rolipram

(Potency10)

The incorporation of

larger ring systems

may be used to

produce analogues

that are resistant to

enzymic attack.

NHCO

O

N

S

HOOC

NHCOCH 2

O

N

S

HOOC

CH 3

CH 3

CH 3

CH 3

Benzylpenicillin

(notb-lactamase

resistant)

Diphenicillin

(b-lactamase

resistant)

Removal of ring

systems has been

used to produce

analogues of naturally

occuring active

compounds.

C

N O

OC 2 H 5

CH 3

CH 3

N

O

OH

OH

Morphine (Narcotic

analgesic)

Pethidine (Narcotic

analgesic)

74 THE SAR AND QSAR APPROACHES TO DRUG DESIGN