strategy for drug design

1. BIOISOTERISM:A useful strategy for drug design
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2.  In medicinal chemistry, bioisosteres are chemical substituents or
groups with similar physical or chemical properties which produce
broadly similar biological properties to another chemical compound.
In drug design ,the purpose of exchanging one bioisostere for another
is to enhance the desired biological or physical properties of a
compound without making significant changes in chemical structure.
The main use of this term and its techniques are related to
pharmaceutical sciences. Bioisosterism is used to reduce toxicity,
change bioavailabilty, or modify the activity of the lead compound, and
may alter the metabolism of the lead.
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3. Introduction
"Compounds or groups that possess near-equal molecular shapes and
volumes, approximately the same distribution of electrons, and which
exhibit similar physical properties."
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4. Why Bioisosteres?
Many properties can be modulated with appropriate
bioisosteres:
• Improved selectivity
• Fewer side effects
• Decreased toxicity
• Improved pharmacokinetics: solubility/hydrophobicity
• Increased metabolic stability
• Simplified synthetic routes
• Patented lead compounds
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5. The development and application of bioisosteres have been adopted as a
fundamental tactical approach useful to address a number of aspects
associated with the design and development of drug candidates.
 Improving potency
 Enhancing selectivity
 Altering physical properties
 Reducing or redirecting metabolism
 Eliminating or modifying toxicophores
 Acquiring novel intellectual property
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7.  APPLICATION OF CLASSICAL BIOISOSTERISM IN DRUG DESIGN.
Replacement of monovalent atom.
 Example
 The substitution of hydrogen atom by fluorine is the one of the most
commonly employed monovalent isosteric replacement. Steric
parameter for hydrogen and fluorine are similar.
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9. Isosteres of carboxylic acid have been studied extensively.
These studies have typically focused on
 Enhancing potency
 Reducing polarity
 Increasing lipophilicity
 (improve membrane permeability)
 Enhancing pharmacokinetic properties
 Reducing the potential for toxicity
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10. Angiotensin II receptor antagonists provide instructive insight into
carboxylic acid isostere design, since binding affinity to receptor in a
series of biphenyl acids is quite sensitive to the identity of the acidic
element.
COOH isosteres in Angiotensin II receptor antagonists
Pharm. Biotechnol. 1998, 11, 29
(DuPont)
Carboxylic acid isosteres
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11. Amide isosteres have typically been of interest as a means of
modulating polarity and bioavailability, while ester isosteres
have frequently been developed to address metabolism issues
since esters can be rapidly cleaved in vivo.
Synopsis of amide and ester isosteres
Amide and ester isosteres
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12. Phenyl ring can often be replaced by a hetero aromatic ring or a
saturated ring which may improve efficacy, lipophilicity and
specificity of binding.
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13. The introduction of a pyridine ring was probed systematically with
the objective of reducing metabolism of the phenyl ring and toxicity
of metabolites.
N substitution for CH in Phenyl ring
J. Med. Chem. 2009, 52, 7778
(Bristol-Myers Squibb)
Phenyl ring isosteres
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14. Cyclopropane was explored as mimetic of the phenyl ring in an effort
to identify compounds with reduced molecular weight and a lower
lipophilicity.
Cyclopropane as phenyl isosteres
Bioorg. Med. Chem. Lett. 2008, 18, 4118
(Bristol-Myers Squibb)
Quantum calculation of biphenyl and
phenylcyclopropyl moieties
Phenyl ring isosteres
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15. How Are Bioisosteres Used in Practice?
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16. The design and application of isosteres have inspired medicinal
chemists for almost 80 years, fostering creativity toward solving
a range of problems in drug design, including understanding
and optimizing drugs – target interactions and specificity,
improving drug permeability, reducing or redirecting
metabolism, and avoiding toxicity.
As an established and powerful concept in medicinal chemistry,
the application of bioisosteres will continue to play an
important role in drug discovery.
Isosterism can also contribute to the productive application in
the design and optimization of catalysts on organic chemistry.
Summary
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17.  It is taken a lot of time to change the drug design.
It is a platform where we can change a drug to newer drug.
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18. REFERENCES:
1: Burger, A. A Guide to the Chemical Basis of Drug Design, NY, EUA,. Wiley,
1983; p. 24-29.
2: Stenlake, J. B. Fondations of Molecular Pharmacology 1979, Vol The
Chemical Basis of Drug Action, Londres, Inglaterra,Athlone Press, p. 213-290.
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