LeadOptimization

1. STRUCTURE – ACTIVITY RELATIONSHIPS
 Structure–activity relationships are usually determined by making minor
changes to the structure of a lead to produce analogues and assessing the
effect these structural changes on biological activity.
 Stereochemistry and drug design
LEAD OPTIMIZATION
 It is now well established that the shape of a molecule is normally one of the
most important factors affecting drug activity.
 Consequently, some structural features stereoisomers, which can exhibit different
potencies, types of activity and unwanted side effects.
 This means that it is necessary to pharmacologically evaluate individual
stereoisomers and racemates.
 Consequently, one must take into account all these stereochemical features
when proposing structures for potential leads and analogues.

2.  Thalidomide was developed in the 1950s as a sleeping pill and was originally
marketed as its racemate. This drug was found after use to be teratogenic,
causing fetus (foetus) abnormalities.
 Further research work showed that it was the S-enantiomer that had the
teratogenic properties while the R-enantiomer was a sedative with no
teratogenic properties.
Example 1

3.  Levorphanol is an analgesic.
 Dextrorphan, the optical antipode of (−)-levorphanol, is not an analgesic at all,
but a very effective antitussive (cough suppressant).
Example 2

4.  Both (R)- and (S)-propranolol are antihypertensive agents.
 But, the (S)-enantiomer is 130-fold more potent than the (R)-enantiomer.
Example 3

5. Quinine is an anti-malarial drug, where its enantiomer, quinidine is an anti-
arrhythmatic agent.
Example 4

6. Example 5
Z E
 Both E- and Z-isomers are anti-histamine agents.
 But, the E-isomer is more potent than the Z-isomer.

7.  Functional group transformation

9. Example 1
 Promethazine is an anti-histamine agent.
 Promazine is an anti-tranquilizer.
 Variation in alkyl chain

10. Example 2
 R= -CH3 , morphine, an analgesic.
 R= -CH3 > -CH2CH3 > -CH2CH2CH3; as the chain length increases the
analgesic activity decreases.
 When R= -CH2CH2CH2CH3, the analgesic activity is zero.

11.  Position of the functional group
 Benzopyrans having sulfonamide substituent at positions 6, 7 and 8 were
synthesized and screened for anti-arrythmatic activity.
 Best anti-arrythmatic activity was observed when the sulfonamide
substituent was at position 7 of the aromatic ring .

12. Simplification tactics have been used successfully with the alkaloid cocaine.
Cocaine has local anaesthetic properties, and its simplification led to the
development of local anaesthetic, procaine, which could be easily synthesized
in the laboratory.
 Simplification or Fragmentation of Lead compound

13.  Structurally distinct yet biofunctionally equivalent molecular fragments are
referred to as bioisosteres.
 Isosteres are functional groups that have little impact on biological activity
when one is exchanged for another.
 A bioisosteric drug is a drug molecule that arises from the replacement of
either an atom or a group of atoms with a biologically equivalent atom or
group of atoms to create a new molecule with pharmacological properties
similar to those of the parent molecule.
 A good drug should be absorbed, distributed, metabolized, and eliminated in
a desirable fashion.
 Isosteric substitutions are intended to impact how the drug gets to and from
the site of action.
 Ideally, an isosteric replacement will improve the lead’s pharmacokinetics
without drastically reducing target binding.
 Bioisosterism

14.  Classical bioisosteres are functional groups that possess similar valence electron
configurations.
 Non-classical bioisosteres are functional groups with dissimilar valence electron
configurations; for instance, a tetrazole moiety may be used to replace a
carboxylate group.

17.  A traditional isostere, or classical isostere, is an atom or group of atoms with
similar spatial requirements. Exchanging one for another imparts little change on
the shape and volume of the molecule and therefore should not affect the binding
(pharmacodynamics) of a compound.
 Changing one isostere for another, however, may impact pharmacokinetics in
any number of ways, including changing lipophilicity and introducing or removing
potential sites for metabolism.

18.  Many isosteric analogues of chlorpromazine (11.29) have been prepared (Figure
11.5).
 Consistent with the theory behind isosteres, analogues 11.30 and 11.31 retain the
activity of chlorpromazine. Compound 11.32, however, is inactive.
 This demonstrates that isosteres, while they are intended to retain the same level
of activity, do sometimes have a significant impact, either positive or negative, on
potency.
 When exchanged for one another, some functional groups may seem different in
terms of their steric sizes, and yet they provide a new analogue with properties
similar to the original. These groups have become known as bioisosteres, or
nonclassical isosteres.

19.  Bioisosteres can seem strange and nonobvious. For example, a bioisostere for a
carboxylic acid is a tetrazole ring.
 Although a carboxylic acid and tetrazole ring may appear to be completely
different, tetrazole has a pKa that is similar to a carboxylic acid (4.9 vs. 4.2,
respectively). Therefore, tetrazole imitates the charge state of a carboxylic acid in
the body.
 From a drug design standpoint, carboxylic acids carry at least one
disadvantage—they undergo phase II conjugations to form glucuronides that are
readily filtered from the bloodstream by the kidneys. Glucuronide formation can
dramatically decrease a drug’s half-life, which is generally not a desired outcome
when one is developing a drug.
 Tetrazoles do not undergo phase II conjugations. If a carboxylic acid in a lead is
found to cause metabolic instability, then replacement of the acid with a tetrazole
ring may provide a more inert compound and preserve strong target binding.
 Losartan (Cozaar, 11.33) and valsartan (Diovan, 11.34) contain tetrazole rings to
avoid metabolic problems associated with the corresponding carboxylic acids.

21.  Another example of modulating metabolism with bioisosteres is the replacement
of hydrogen with fluorine in the development of ezetimibe (Zetia, 11.21).
 The fluorine atoms block phase I oxidation of two of the aromatic rings in the drug.
Blocking metabolism at the 4-position of the ring prolongs the effective duration of
the drug in the body. Fluorine is particularly useful in this role because it is similar
in size to hydrogen.
 The van der Waal’s radius of hydrogen is 1.2 Å, while fluorine’s is 1.35 Å. Fluorine
does not introduce steric bulk but does decrease the electron density in the ring
sufficiently to suppress oxidation.