Drug Design: Pharmacokinetic Design Flashcards
How is biological activity evaluated?
Using in vitro testing methods
What is pharmacokinetic drug design?
Drug design based on favourable pharmacokinetic drug interactions in the body
What is the overall journal taken by an orally active drug?
Dissolution in GIT (drug just be water soluble)
Entry into stomach (drug must be stable to withstand attack of stomach acid and digestive enzymes)
Absorption into blood supply (drug must be sufficiently fat soluble)
Travel to target in blood supply (drug can be absorbed by fat tissue if lipophilic bound to plasma proteins or nucleic acids if ionic, or excreted by kidneys if polar)
Crossing of blood brain barrier (drug needs to be lipophilic)
What is the main factor affecting bioavailability?
The first pass effect, where a proportion of the drug in carried to the liver to be metabolised before it reaches the target site.
Why may an analogue exhibiting the best drug target interactions may not be the best drug use clinically?
It may only show weak in vivo activity
The drug may never reach the target due to chemical/metabolic stability and unbalanced hydrophilicity/hydrophobicity
Why must an orally active drug be chemically and metabolically stable?
Drugs taken orally must be able to survive in the acidic conditions of the stomach and all must be stable in aqueous solution
They must also be stable to digestive and metabolic enzymes
Why must drugs be the right hydrophilic lipophilic balance?
Drugs which are too polar are easily excreted by the kidneys, thus cannot cross into cells.
Drugs which are too lipophilic may not dissolve in water and are easily absorbed by fatty tissues of the body instead of reaching their site of action.
How can we increase the resistance of the drug to hydrolysis and metabolism?
Incorporate steric shields Use of bioisosteres Use of metabolic blockers Shifting substituents Introducing an easily metabolised functional group
How does the incorporation of steric shields increase drug resistance to hydrolysis and metabolism?
Some groups like esters and amides are prone to hydrolysis.
By adding bulky alkyl groups, we can hinder the approach of nucleophiles thus blocking hydrolysis
E.g. Tert butyl group acting as a steric shield to protect the terminal peptide bond of D1927- an antirheumatic agent.
How does the use of a bioisostere increase drug resistance to hydrolysis and metabolism?
A bioisostere is a placement for a functional group that does not affect the biological activity of a molecule.
It does not necessarily resemble the replaced functional group to a high degree, but may be more stable.
E.g. Pyrrole is not classically isosteric with an amide but its biological activity is retained, thus used on sultopride (dopamine antagonist) to form Du122290 which is a more stable dopamine antagonist
How does the use of metabolic blockers increase drug resistance to hydrolysis and metabolism?
Certain positions of a molecule are easily modified by metabolic enzymes,
If highest posititions are blocked then metabolism may also be prevented.
E.g. In megestrol acetate is an oral contraceptive. It has a prime site which CYP450 likes to attack. Hydrolysis of this results in excretion of the comkoound. However, the Introduction of a methyl group blocks this metabolism
How can shifting substituents increase resistance of a drug to hydrolysis and metabolism?
An unstable group may be important to binding and thus cannot be removed.
In some cases moving the group to another position on the molecule can retain the activity however there is also a chance that the new analogue no longer fits in the active site of the metabolic enzyme
In the case of salbutamol, they managed to retain the hydrogen bond interactions between the compound and receptor even after moving the unstable group to another position, resulting in a common clinically used drug for the treatment of asthma
How can introducing groups that are easily metabolised increase drug resistance to hydrolysis and metabolism?
Introducing more easily metabolised groups may allow enzymes to metabolise those as opposed to metabolising the unstable group in the drug molecule.
E.g. By adding a methyl group on an aromatic ring which can be easily metabolised.
Why do we improve solubility and permeability?
If drugs are too polar they are easily excreted and will not cross cell membranes easily
Drugs of high lipophilicity are not soluble in aqueous solutions and may be taken up by fatty tissue.
Varying the type or substitution patterns in a drug lead compound can be used to modify the hydrophilic hydrophobic balance
Polar groups can be masked to improve lipophilicity
What may result from the masking of pool groups?
Polar groups may be involved in binding to the target so masking them may decrease activity
