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Module 3B - SAR2 - Coggle Diagram
Module 3B - SAR2
pKa of a drug controls water solubility
Solubility in aq. environments is pH dependent
Most drugs contain ionizable FG's (acidic or basic)
75% of drugs are bases
20% of drugs are acids
5% of drugs are non-ionizable
ionization increases water solubility
neutral forms are more membrane-permeable
For acids
the value refers to the acid form
neutral when pH < pKa
charged when pH > pKa
For bases:
the value refers to the corresponding conjugate acid
charged when pH < pKa
neutral when pH > pKa
Certain FGs can act as either an acid or a base (
amphiprotic
), depending on their chemical environment
Lipinski's Rule of 5
What is it?
rapid way to evaluate drugs
predicts the likelihood of poor absorption or permeation
based on statistical analysis of compounds from the World Drug Index
fast, cost-free, well-documented and widely used in early drug discovery
How does it work?
compounds that meet 2+ criteria are not likely to be well absorbed into the body
What are the criteria?
More than 5 H bond donors (OH's and NH's)
H-bonds increase water solubility
too many H-bonds make it difficult to cross lipophilic membrane
More than 10 H bond acceptors (N's & O's)
molecular weight >500
large molecules tend to be less soluble
large molecules cross membranes less easily
Calculated LogP > 5
water solubility
decreases
as lipophilicity
increases
Why is lipophilicity important for drugs?
effective drugs must maintain a balance between lipophilicity and hydrophilicity
hydrophilic enough to dissolve in the aq biological fluids and be transported
lipophilic enough to cross biological membranes and access their target sites within the body
How is lipophilicity measured?
LogP
LogP = Log ( [Drug_octanol] / [Drug_water] )
log of the partition coefficient between octanol and water for the neutral (non-ionized) form of a drug
High LogP = compound is more lipophilic
Low LogP = compound is more hydrophilic
Advantages: well establishes, correlates strongly with Lipinki's Rule of 5
Disadvantages: each molecule may require a different buffer system, measurements are performed under non-physiological conditions
LogD
log of the partition coefficient between octanol and water for a drug at a specific pH (usually 7.4)
LogD can replace LogP as a more realistic measure for ionizable compounds
optimal range: 1 < LogD_7.4 < 3
Advantages: methods are well established, easier to measure (fixed pH), correlates to rule of 5, physiological relevance
Disadvantages: less widely used than LogP (modern use only)
Two common measurement methods:
Shake-Flask (solution method)
prepare a standard drug solution in water
add an equal volume of octanol
shake thoroughly to reach equilibrium
separate the two layers and measure the drug concentration in both phases
High-Performance Liquid Chromatography (HPLC)
inject the sample into a specialized HPLC column calibrated with compounds of known LogP
Retention time increases with lipophilicity; this correlation is used to estimate LogP