BIOISOSTERSM

strategy for drug design

1. BIOISOTERISM :A useful strategy for drug design PHARMACEUTICAL CHEMISTRY 1

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. 2 Definition

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 ." 3

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 4

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 5

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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. 7

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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 9

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 10

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 11

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 . 12

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 13

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 14

15. How Are Bioisosteres Used in Practice? 15

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 16

17. I t is taken a lot of time to change the drug design. It is a platform where we can change a drug to newer drug. 17

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. 18