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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5434_Библиотеки_им_академика_М_И_Перельмана
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lead compound. The use of bioisosteres and the introduction of structural changes to
the lead compound allows the chemist to alter the compound’s size, shape, electronic
distribution, polarizability, dipole, polarity, lipophilicity, and pK
a
, while retaining po-
tent target engagement. Therefore, the bioisosteric approach can be used for the ratio-
nal modification of a lead compound toward a more attractive therapeutic agent with
improved potency, selectivity, altered physical, metabolic, toxicological properties
with the bonus of generating novel intellectual property.
Fig. 4.33: Isosteric substitutions of the peptide bond.
72 4 Optimization of prototypes
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4.8 Exercises
1. Indicate the molecular modification criteria used in the design of the following
drugs, giving a reasoned explanation:
(a)
(b)
Fig. 4.34: Met-enkephalin and morphine.
4.8 Exercises 73
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(c)
(d)
(e)
(f)
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(g)
(h)
(i)
(j)
4.8 Exercises 75
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(k)
(l)
(m)
(n)
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2. Given the following pairs of structures, indicate if they are isosteres, homologues,
or vinylogues:
(a)
(b)
(c)
(d)
(e)
4.8 Exercises 77
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(f)
(g)
(h)
(i)
(j)
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(k)
3. Explain the purpose of the molecular modification achieved when switching from
one drug to the other:
(a)
(b)
(c)
4.8 Exercises 79
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(d)
(e)
(f)
(g)
80 4 Optimization of prototypes
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(h)
4.8 Exercises 81
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