Physical Properties 2 Lecture Flashcards
Log P is
partition coefficient
clogP
calculated partition coefficient
LogD
Distribution coefficient
Define lipophilicty
Fat-liking
Decrease lipophilicity, increase hydrophilicity
Define ionized
water soluble, not very lipophilic because it forms strong H bonds
Hydrophobic bonding is?
Drugs are typically hydrophobic molecules
Binding sites = hydrophobic too
Like attracts like
What drives hydrophobic bonding?
Proximity and H or ionic bonding
Anchorage
Entropy gains (when water molecules are displaced from the active site)
Enthalpy gains may result from?
van der Waals bonding between: alkyl, aryl or halogen groups & pi-pi stacking (phenol rings)
Define Entropy gains
Increased disorder
Gains energy
Achieved when water is displaced form the active site
Favors hydrophobic interactions bc it allows more disorder
Gibbs Free Energy equation?
Delta G = delta H - T*delta S
Delta G: free energy the system has
Delta H: change in enthalpy
Delta S: Entropy
Negative delta S means?
Increased order (reduced entropy)
Negative delta G means?
gains energy
Nonpolar surface into water?
Disturbs network of water-water H bonds
Causes reorientation of the network of H bonds to give fewer but stronger, water-water H bonds close to the nonpolar surface
Lower IC50 means?
more active the compound (lipophilicity increases)
What is the hydrophobic effect?
Compound is too lipophilic, so it may be insoluble in aqueous media, bind too strongly to plasma protein (no desired effect), distribute into lipid bilayers and unable to reach the inside of the cell
Compound is too polar, it may no absorbed through the gut wall due to lack of membrane solubility
Define logP
measure of the relative affinity of a molecule for the lipid and aqueous phases in the absence of ionisation
MEASURE OF NEUTRAL COMPOUNDS
1-Octanol is a frequent lipid phase because?
It has polar and nonpolar regions
P is fairly easy to measure and often correlates well with biological properties
Predicted fairly accurately using computation models
As logP increases…?
lipophilicity increase, hydrophobicity increases, more chances of van der Waals interactions
Increase binding to enzyme/receptor
Increased absorption through membrane
Less free drug to act
Define distribution coefficient
Effective lipophilicity of an ionized compound at a given pH
Change pH = change logD
Increased ionization = decrease logD
Low logD = water soluble
High logD = not water soluble, hydrophilic, ionized species, acid
Distribute into octanol?
NO IONIZED COMPOUNDS
pH behavior with amphoteric drugs?
Low pH: OH stays but proton added to the amine
As pH increases: more alkaline –> OH gives away H (ionized species)
Increasing logD?
Increase lipophilicity (stronger binding) Decrease water solubility (can't get into the circulation) Decrease ionization
Add oxygen to a molecule ALWAYS?
decrease lipophilicity because of HBA –> H bond with water –> more soluble
Add a CF3 group to a molecule?
Increase lipophilicity
Replacing H with a halogen?
Increases the lipophilicity
Addition of a hydroxyl group
Decreases the lipophilicity
Removal of the quinoline N to give a carboxcyclic ring
Greatly increases lipophilicity
Replacing a quinoline with a benzene ring will?
Increase the lipophilicity
What increase lipophilicity?
Methyl Ethyl Higher order hydrocarbon Trifluoromethane Cl Br CH2Cl C2H4Br Phenyl rings Carbocyclic rings
Why is CF3 so lipophilic?
Cannot be ionized
F holds electrons so tight, can’t form H bonds
Extremely EWG, exert this effect across several bonds, to stabilize negative charge or prevent H bonding to a lone pair
Structural features that reduce lipophilicity
Polar functional groups (contain electronegative atoms)
Groups that ionize (form stable anions and cations): OH, NH2, COOH, OMe, N(CH3)2, CONH2
