2. ï 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:
âą Improved selectivity
âą Fewer side effects
âą Decreased toxicity
âą Improved pharmacokinetics: solubility/hydrophobicity
âą Increased metabolic stability
âą Simplified synthetic routes
âą 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.
ïŒ Improving potency
ïŒ Enhancing selectivity
ïŒ Altering physical properties
ïŒ Reducing or redirecting metabolism
ïŒ Eliminating or modifying toxicophores
ïŒ Acquiring novel intellectual property
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7. ï APPLICATION OF CLASSICAL BIOISOSTERISM IN DRUG DESIGN.
Replacement of monovalent atom.
ï Example
ï 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
ïŒ Enhancing potency
ïŒ Reducing polarity
ïŒ Increasing lipophilicity
ïŒ (improve membrane permeability)
ïŒ Enhancing pharmacokinetic properties
ïŒ 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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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 â 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. ï 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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Hinweis der Redaktion
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.
This sulfonamide moiety confers a 3-fold increase in potency compared to the carboxylic acid analog.
Furthermore, the efficacy of the squaric acid analog and the tetrazole analog is superior to both the carboxylic acid and the sulfonamide.
Although the efficacy of squarate was lower than the tetrazole analog,this squarate reduced blood pressure in hypertensive rats following oral administration.
Here, you can see the synopsis of amide and ester isosteres.
My first choices are these heterocycles.
The introduction of a pyridine ring was probed systematically with the objective of reducing metabolism of the phenyl ring and toxicity of metabolites.
In HIV-1 attachment inhibitor, the 4,7-dimethoxy substituted indole is a highly potent antiviral compound that is metabolized in vivo, leading to the potential for quinone formation, a known toxicophore.
Then 6-aza analog offered improved aqueous solubility and abolished the potential for reactive quinone formation should demethylation occur, which in this series would afford the nontoxic amide.
Cyclopropane was explored as mimetic of the phenyl ring in an effort to identify compounds with reduced molecular weight and lower lipophilicity.
In FXa inhibitor, the cyclopentane analog demonstrated lower lipophilicity and markedly improved potency compared to the biphenyl analog.
Quantum mechanical calculation supported that the phenylcyclopropanes exist in the perpendicular conformation.
This perpendicular conformation mimics the biologically active conformation of the ortho-substituted biphenyl moieties.
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 â 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.