Chapter 9 Structure Activity Relationships (EXAM 3) Flashcards
SAR: Enhancing pharmacologic activity
f.e. by enhancing solubility by adding an EWG to sulfonamide (acidic functional group)
a EWG make an acidic functional group more acidic -> solubility increased (lower the pKa)
SAR: Enhancing binding specificity
-make an agonist: structure closely resembles the original structure - only a small change
-make an antagonist: structure contains a greater change, still similar enough to bind but not activate the receptor
SAR: Enhancing ADME
the stability of the amide group (vulnerable to hydrolysis) determines if the structure is acid stable or not
-Acid-labile (can give orally - degraded)
-Acid-stable (can’t give orally bc they will survive in the stomach): EWG draws electrons away and makes the amide more stable
SAR: Strucutral Simplification
make a complex lead easy to synthesize
-remove functional groups outside the pharmacophore
-simplify the carbon skeleton
-remove the chiral center
Why does removing chiral carbon make the drug easier to synthesize?
each enantiomer needs to be proven to be safe to administer
->takes cost and time
What is Homologation?
-changes in carbon load
-can make a drug more water-soluble
-addition/removal of rings or methylene groups
How does increasing carbon load change the property of a drug?
-alter receptor selectivity
-can convert agonist to antagonist
Carbon skeleton: Conformational Restriction
-changes in flexibility & reactivity
-reduce the number of possible conformational isomers
-reduce possible side effects
-change from cyclohexane (chair form - no double bunds) to a benzene ring to reduce flexibility/ increase rgidity
Modification of functional groups
-> Addition of a halogen
increases fat solubility –> accumulation in fat tissue
-> if the drug is supposed to work in the brain
-> the halogen is more reactive and can lead to Phase I reaction: dehalogenation
Modification of functional groups
-Adding hydroxyl groups
-more accessible to Phase II
good/bad -> QUICKER clearance/reduce half-life
-increase water solubility/decrease lipophilicity
good/bad -> depending on what the target is
f.e. Pseudoephedrine with OH doesn’t have as much access to the brain compared to Methamphetamine
Modification of functional groups
-Addition of ionizable groups
-Allow the formation of salts
-increases water solubility and polarity
-Note: aromatic amines are avoided (toxicity)
-Adding COOH: is a good ligand for Zinc
Modification of functional groups
-Addition of hydrolyzable groups
Ester & amides can act as a prodrug
-mask polar groups to make it more lipophilic
-esterases will break ester bonds and expose the
Modification of functional groups
Sulfur containing groups
-Adding sulfides and thiols
-> can lead to the oxidation of thiols and sulfides
->can lead to a disulfide bridge between two sulfides (deactivates the drug)
-may taste metallic, sensitive for some patients
-> Therefore sulfides are generally avoided
Exchange of functional groups
Isosteres: atoms or groups with the same electron distribution & same physical/chemical property
Bioisosters: functional group replaced by another one, but retains biological activity
Quantitative Structure-Activity Relationships
QSAR
-a mathematical relationship that describes properties and how the drug might behave in vivo
Biological activity = f( parameter)
the more data I have the better predictions can be made
