removal of dimethylamino group
What biosteric modification changed aminopyrine's carcinogenic effect; resulting in Propylphenazone?
Bioisosteres
-substituents or groups with similar physical or chemical properties which produce broadly similar biological properties in a chemical compound.
monovalent, divalent, trivalent, tetrasubstituted atoms, ring equivalents
What groups belong to classical bioisosteres?
cyclic and noncyclic isosteres, exchangeable groups
What groups belong to nonclassical bioisosteres?
a,d
What element is an isostere of H?
a) Fluorine
b) Oxygen
c) Magnesium
d) Deuterium
to block metabolically liable site in hopes that it does not impair binding to target
Why do we use F as an Isostere?
d
What is the most conservative example of biosterism in regards to H atom?
a) Fluorine
b) Oxygen
c) Magnesium
d) Deuterium
lowers pKa; more acidic
What effect does fluorine have on pKa?
can redirect metabolic pathways
How does replacing Hydrogen with Deuterium affect metabolism?
C-D
Which bond is more stable?
C-H or C-D
decreases CYP2D6 activity; causing this compound to be metabolized faster; less chance for ddi
How did Deuterium resolve some of the implications associated with Paroxetine?
4; it is acidic due to it being next to ketones
How many chiral centers are in this compound? Why does S get racemized and not the other chiral centers?
slows epimerization
How does adding deuterium affect this compounds metabolism?
huntington's disease; adding d prevents o-demethylation increasing drug half-life
What disorders are these drugs used to treat? How does adding deuterium improve this drug?
Tetrazine; carboxylic acid
What is the name of this functional group? What isostere group does it belong to?
D & F
What are isosteres of H?
sulfonamide; carboxylic acid
What is the name of this functional group? What isostere group does it belong to?
carbamate; carboxylic acid
What is the name of this functional group? What isostere group does it belong to?
increase binding affinity by adding groups with more HBA; tetrazine
What is the goal of replacing carboxylic acid with the following isosteres? Which isostere gives us the best binding affect?
Nonclassical bioisosteres
-structurally distinct, usually comprised of different atoms and exhibit different steric and electronic properties.
prevented thymidylate synthase from metabolizing the drugs
How did the addition of Fluorine in 5-Fluorouracil & Trifluridine improve it?
increase binding by replacing cooh with groups that have more hba's
What are uses of carboxylic acid isosteres?
increases pka; more acidic and faster clearance
What does Fluorine offer as an isostere?