Organic Chemistry

1222 CHAPTER 30 The Organic Chemistry of Drugs

with its long chain and polar head group, it is a good model of a biological membrane.

When the amount of drug dissolving in each of the layers was measured, it turned out

that they all had a similar distribution coefficient(the ratio of the amount dissolving in

1-octanol to the amount dissolving in water). In other words, the distribution coefficient

could be related to biological activity. Compounds with lower distribution coefficients—

more polar compounds—could not penetrate the nonpolar cell membrane; compounds

with greater distribution coefficients—more nonpolar compounds—could not cross the

aqueous phase. This meant that the distribution coefficient of a compound could be used

to determine whether a compound should be tested in vivo. The technique of relating a

property of a series of compounds to biological activity is known as a quantitative

structure–activity relationship (QSAR).

Determining the physical property of a drug cannot take the place of in vivo testing

because how the drug will behave once it reaches a suitable receptor cannot be pre-

dicted by the distribution coefficient alone. Nevertheless, QSAR analysis provides a

way to lead chemists to structures with the greatest probability of having the desired

biological activity. In this way, molecular modification that would lead to compounds

without the desired activity can be avoided.

In the following example, QSAR was useful not only in determining the structure

of a potentially active drug but also in determining something about the structure of

the receptor site. A series of substituted 2,4-diaminopyrimidines, used as inhibitors of

dihydrofolate reductase (Section 25.8), was investigated.

The potency of the inhibitors could be described by the equation

where and are substituent parameters.

The parameter is a measure of the electron-donating or electron-withdrawing

ability of the substituents R and The negative coefficient of indicates that poten-

cy is increased by electron donation (Chapter 17, Problem 75). The fact that increasing

the basicity of the drug increases its potency suggests that the protonated drug is more

active than the nonprotonated drug.

The parameter is a measure of the hydrophobicity of the substituents. Potency

was found to be better related to when the value for the more hydrophobic of the

two substituents was used, rather than the sum of the values for both substituents.

This finding suggests that the receptor has a hydrophobic pocket that can accommo-

date one, but not both, substituents.

In a search for a new analgesic, the potency of the drug was found to be described

by the following equation, where HAindicates whether R is a hydrogen bond acceptor

and where Bis a steric factor:

Analysis indicated that the vinyl substituted compound should be prepared.

In a search for a drug to be used to treat leukemia, a QSAR analysis showed that the

antileukemic activity of a series of substituted triazines was related to the electron-

O

R

N

COOH

potency = − 4.45 − 0.73HA + 6.5B − 1.55(B)^2

p

p p

p

R¿. s

s

s p

potency=0.80p-7.34s-8.14

N

a 2,4-diaminopyrimidine

N

NH 2

H 2 N

R

R′

Tutorial:

Quantitative structure–

activity relationship

(QSAR)

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