Medicinal Chemistry

This two-step strategy enables the drug to be optimized first for its ability to bind to a
receptor site and then for its ability to actually travel to that receptor site.
Optimizing the lead compound for the pharmacodynamic phase is likewise
approached via a two-step strategy:

1. Synthesizing analogs of the lead compound


2. Correlating analog structure with bioactivity via quantitative structure–activity rela-
   tionship (QSAR) studies

This two-step strategy starts with the synthesis of numerous analogs of the lead compound.
This is meant to explore the structural diversity of the lead compound. Next, QSAR stud-
ies are employed to correlate these structural diversities with bioactivity. The results of the
QSAR studies are then used to design new and, hopefully, improved analogs.

3.4.1 Analog Synthesis

Classical structure modifications have been the mainstay of drug optimization since the
earliest days. As emphasized earlier at several points, structural modifications expressed
in organic chemical terms are really only symbols for modification of the physicochem-
ical properties of various structures. Nevertheless, the medicinal chemist usually thinks
in terms of structure, since that is the language of organic synthesis. It is therefore appro-
priate to deal with such an approach, provided one keeps in mind that it is somewhat
obsolete because it is twice removed from the arena of drug–receptor interactions.

3.4.1.1 Variation of Substituents via Homologation

The first approach is to vary substituents. The variation of substituents can follow many
directions. It can be used to increase or decrease the polarity, alter the pKa, and change the
electronic properties of a molecule. Exploration of homologous series is one of the most
often used strategies in this regard, because the polarity changes that are induced are very
gradual. Homologation is a standard first approach to substituent variation; indeed, a
“standard joke” in medicinal chemistry is to pursue the “methyl, ethyl, propyl, ... futile”
series of analogs. Despite the somewhat facetious nature of this statement, there are many
examples in which homologation is important to drug design.
The case of the antibacterial action of aliphatic alcohols has been known in detail for
many years; an increase in chain length leads to increased activity, with a sudden cutoff
point at C 6 –C 8 , due to insufficient solubility of these homologs in an aqueous medium
because of their high lipophilicity. On the other hand, local anesthetics depend on lipid
solubility in the membrane, and the duration of anesthesia produced by the nupercaine
derivatives varies between 10 and 600 minutes for a series of alkyl substituents ranging
from a simple -H to -n-pentyl. Another well-known example is the profound qualitative
change in action between promethazine (3.5), an H 1 -antihistaminic drug in which two
-CH 2 - groups separate the ring and side-chain nitrogens, and promazine (3.6, an analog
of promethazine), which has three methylene groups and predominantly exhibits tran-
quilizing properties. Higher homologs can, on occasion, become antagonists of the lower
members of a series.

DESIGNING DRUG MOLECULES TO FIT RECEPTORS 135