Bioisosteres Flashcards
Whta should be considered to improve lead compounds?
Chemical stability, metabolic stability and an appropriate balance between hydrophobicity and hydrophilicty,
What is the importance of drugs being hydrophobic and hydrophilic?
Hydrophobocity is important as the drug needs to be able to cross the cell membrane. Hydrophilicty is important as the drug needs to be able to get into solution.
How would you lower CNS side effects for a drug that has chloride ions?
Replace chlorine with fluorine. Fluorine is more electronegative so will not the cross the BBB as easily, so fewer side effects.
How can an ester become stabilised?
Opt for a carbamate or an amide . A carbamate is more stable than an ester because the nitrogen in NH2 is able to provide metabolic and chemical stability.
Add methyl groups (Procaine does not have have any, but Lidocaine does and hinders hydrolysis by esterases.
Define a metabolic blocker.
Drugs with a methyl group can be metabolised rapidly to form OH groups. How can this be stooped?
Blocking sites which are susceptible to drug metabolism
Replace the methy group with a halogen.
Define a bioisostere
Bioisosteres are substituents or groups with similar physical and chemical properties, which produce broadly bilogical properties in the drug. The purpose is to be able to replace one group or substituent with another, resulting in the enhancement of the desired physical or biological properties.
What factors should be considered whewn selecting a bioisostere?
Group size, conformation, inductive and mesomeric effect, polarisability, H-bonding, pKa, hydrophobicity, reactivity and stability.
Give biosteres for the following atoms/groups:
1) H
2) OH
3) R-SH
1) H can be replaced by F - similar size
2) OH can be replaced by NH2- harder to protonate
3) R-SH can be replaced by R-OH as R-SH is prone to oxidation to a disulfide or even an acid.
Pair the atoms /groups that have similar atom size:
1) H a) Cl
2) C b)Br
3) CH3 c)F
1c - Hydrogen is 120 picometres, Fluorine is 147 picometres
2a - Carbon is 170 picometres, Fluorine is 175 picometres
3b - Hydrogen is 200 picometres, Fluorine is 185 picometres
Would Flourine be found in acids or bases? Why?
Fluorine can be found in bases because fluorine is more electronegative and is therefore more electron withdrawing, weakening the power of the basic functional group. In acids, this characteristic would promote proton loss.
Explain the rationale behind the biosteres of carboxylic acids.
CAs can be replaced by tetrazole or by 2,6- difluorophenol.
CAs are too polar to cross the CNS, tetrazole is not.
2.6- difluorophenol has a higer log P, so less drug is needed as more is going across the BBB. The flourine acts like a carbonyl, a hydrogen bond acceptor.
Describe a bioisotere for amides
The CONH group in amides can be replaced by CF3NH, withdrawing electron density, thus lowering the basicity of the amine. However, not to the extent that he NH is no longer able to accept hydrogen bonds.
