Bioisosteres

1. Bioisosteres Jan.31.2013 Hiroyuki Kobayashi

2. An example of bioisosteres Aminopyrine Marketed as an analgesic and anti-inflammatory drug in 1896. In 1922, It was revealed that Aminopyrine was a carcinogen ! Propylphenazone Developed by Roche in 1951. Bioisosteric modification of dimethylamino group removed its carcinogenic action.

3. Bioisosteres are substituents or groups with similar physical or chemical properties which produce broadly similar biological properties in a chemical compound. What is bioisostere?

4. Bioisosteres are substituents or groups with similar physical or chemical properties which produce broadly similar biological properties in a 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. What is bioisostere?

5. The utility of bioisosteres 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.

6. The utility of bioisosteres 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. The utility of bioisosteres is extending to • Improving potency • Enhancing selectivity • Altering physical properties • Reducing or redirecting metabolism • Eliminating or modifying toxicophores • Acquiring novel intellectual property

7. Classical bioisosteres Classical bioisosteres represent the result of an early appreciation of the concept and encompass structurally simple atoms or groups

8. Nonclassical bioisosteres Nonclassical bioisosteres are structurally distinct, usually comprised of different number of atoms and exhibit different steric and electronic properties.

9. Application of bioisosteres in drug design

10. F as an isostere of H The unique properties of F have led to its widespread application in drug design as an isostere for H, since incorporation of F can productively modulate a range of properties of interest to medicinal chemists. 20% of all drugs are fluorinated compound!

11. F as an isostere of H J. Med. Chem. 2004, 41, 1 (Bayer) Improving metabolic stability One of the strategies to counter low metabolic stability is to block the metabolically liable site with a F substituent and hope that the small F atom will not impair the binding of the target protein.

12. F as an isostere of H Effect on the pKa As the most electronegative atom, F has a very strong effect on acidity or basicity of nearby functional groups.

13. F as an isostere of H J. Med. Chem. 2008, 51, 4239 (Merck) Effect on the pKa As the most electronegative atom, F has a very strong effect on acidity or basicity of nearby functional groups.

14. F as an isostere of H Bioorg. Med. Chem. Lett. 2010, 20, 2572 (Merck) Effect on molecular conformation As a consequence of the high electronegativity of F, the C-F bond is most polarized and can influence conformational bias via intramolecular electrostatic interactions

15. D as an isostere of H Substituting a H atom by D represents the most conservative example of bioisosterism given the similarities between the two isotopes, but there are circumstances in drug design where this change can offer a significant advantage.

16. D as an isostere of H Nature 2009, 458, 269 (Concert) D substitution to modulate metabolism The strategic deployment of D at sites of metabolism where H atom abstraction can disturb metabolism and redirect the metabolic pathway.

17. D as an isostere of H J. Med. Chem. 2009, 52, 7993 (Vertex) D to slow epimerization Deuteration at the labile center shows increased stability toward racemization.

18. Carboxylic acid isosteres 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

19. Carboxylic acid isosteres Synopsis of carboxylic acid isosteres Common isosteres Heterocycle based isosteres

20. Carboxylic acid isosteres Pharm. Biotechnol. 1998, 11, 29 (DuPont) COOH isosteres in Angiotensin II receptor antagonists 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.

21. Carboxylic acid isosteres J. Med. Chem. 2004, 47, 2706 (Aristotle Univ.) 2,6-Difluorophenol as a COOH mimetic The introduction of fluorine atoms the 2- and 6-positions of phenol increase the acidity, prompting the hypothesis that this functionality may function as a lipophilic COOH mimetic.

22. Amide and ester isosteres 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.

23. Amide and ester isosteres 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

24. Amide and ester isosteres Trifluoroethylamines as amide isosteres The trifluoroethylamine can act as an isostere of an amide moiety in peptide-based molecules.

25. Amide and ester isosteres Trifluoroethylamines as amide isosteres The trifluoroethylamine can act as an isostere of an amide moiety in peptide-based molecules. Functional mimicry is based on • Reducing the bascity of the amine without compromising the ability of the NH to function as a H-bond donor • CF3CH(R)NHR’ bond is close to 120o observed with an amide • C-CF3 bond is as polar as C=O bond

26. Amide and ester isosteres Bioorg. Med. Chem. Lett. 2008, 18, 923 (Merck) . Trifluoroethylamines in Cathepsin K inhibitors The trifluoroethylamine is an excellent surrogate for amide bond in the inhibitor of Cathepsin K.

27. Phenyl ring isosteres Phenyl ring can often be replaced by a heteroaromatic ring or a saturated ring which may improve efficacy, lipophilicity and specificity of binding.

28. Phenyl ring isosteres J. Med. Chem. 2009, 52, 7778 (Bristol-Myers Squibb) N substitution for CH in Phenyl ring The introduction of a pyridine ring was probed systematically with the objective of reducing metabolism of the phenyl ring and toxicity of metabolites.

29. Phenyl ring isosteres Bioorg. Med. Chem. Lett. 2008, 18, 4118 (Bristol-Myers Squibb) Cyclopropane as phenyl isosteres Cyclopropane was explored as mimetic of the phenyl ring in an effort to identify compounds with reduced molecular weight and a lower lipophilicity. Quantum calculation of biphenyl and phenylcyclopropyl moieties

30. Phenyl ring isosteres J. Med. Chem. 2012, 55, 3414 (Pfizer) Bicyclo[1.1.1]pentane as phenyl isosteres The bicyclo[1.1.1]pentane motif is ideally suited to dispose two substituents in the required coplanar orientation like p-Ph ring. Bicyclo[1.1.1]pentane and Ph ring include comparable dihedral angles and similar distances between substituents

31. Phosphate isosteres Phosphate play a central role in cellular signaling and consequently are of great interest to medicinal chemists. However the design of molecules that can interfere with phosphate-based processes is recognized as a significant challenge, especially when the resulting compounds must show good cellular penetration and stability.

32. Phosphate isosteres Chem. Comm. 1998, 1087 (Liverpool Univ.) Difluorophosphonate as phosphate isostere Structural and electronic studies have firmly established the fluorinated phosphonates as closely related, hydrolytically and enzymatically stable mimics of the phosphate.

33. Phosphate isosteres HIV-1 integrase inhibitors and phosphate isosterism Mechanism of retroviral integration ①HIV integrase bound to viral DNA via Mg2+ ions and catalyzed the attack of the phosphodiester viral DNA by a H2O molecule.

34. Phosphate isosteres HIV-1 integrase inhibitors and phosphate isosterism Mechanism of retroviral integration ②After translocating to the cell nucleus, the integrase protein promoted the attack of the host DNA.

35. Phosphate isosteres HIV-1 integrase inhibitors and phosphate isosterism Mechanism of retroviral integration ③Result in strand transfer and cleavage of the host DNA.

36. Phosphate isosteres HIV-1 integrase inhibitors and phosphate isosterism Character of HIV-1 integrase inhibitors Integrase inhibitors (Diketo acid) bind to the active site Mg2+ ions in conjunction with viral DNA and acting as mimics of the transition state intermediate.

37. Phosphate isosteres PNAS. 2012, 109, 7, 2251 (Merck) HIV-1 integrase inhibitors and phosphate isosterism Character of HIV-1 integrase inhibitors The pyrimidinedione moiety acts as the diketo acid.

38. Summary 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.

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