Академический Документы
Профессиональный Документы
Культура Документы
y Attempts to identify and quantitate physicochemical properties of a drug in relation to its biological activity or binding y Studies hydrophobic, electronic, and steric properties--either whole molecule or pieces med chemist draws up an equation that quantifies the relationship & allows one to predict (to some extent) the biological activity
Quantitative Structure-Activity Relationships (QSAR) %dv fewer compounds may need to be made ,oweverif compound does not fit the equation, then chemist knows they need to modify the equation
Log P (partition coefficient) Hydrophobicity yP = [drug] in octanol / [drug] in water Vary log P & see how this affects the biological activity. Biological activity normally expressed as 1/C, where C = [drug] required to achieve a defined level of biological activity. The more active drugs require lower concs.
Log P: Hydrophobicity
Log P
Parabolic curve: curve: log 1/C = - k1 (log P)2 + k2 log P + k3
When P small, dominated by log P term When P large, log P squared dominates & so activity decreases
Log P
Note that one is not always measuring biological activity, sometimes binding!
*RELATIVELY FEW DRUGS EXIST WHOSE ACTIVITY IS RELATED TO LOG P ALONE!!! --those that do are the general anesthetics--partition into cell membranes, & thereby affect membrane structure & nerve function --no specific drug-receptor interactions
(anesthetic activity increases in same order) Drugs with Log P values close to 2 should be able to enter the CNS efficiently e.g. barbiturates have log P values close to 2 also; want to make sure log P value is much lower if you dont want possible CNS side effects
P vs. T
P measures drugs overall hydrophobicity & measures drugs transportability T measures the hydrophobicity of a specific region on the drug--hydrophobic bonding to a receptor
T
Possible to calculate the substituent hydrophobicity constant (T) A measure of how hydrophobic relative to H Measure P experimentally for a standard compound with and without a substituent (X). Use this equation: Tx = log Px - log PH
T
Tx = log Px - log PH H is for standard compound positive T = substituent more hydrophobic than H negative T = less hydrophobic than H
Theoretical Log P for chlorobenzene = log P for benzene + T for Cl = 2.13 + 0.71 = 2.84
Theoretical Log P for meta-chlorobenzamide = log P for benzene + T for Cl + T for CONH2 = 2.13 + 0.71 - 1.49 = 1.35
Tables of T
See Table 2.5 Many tables exist for all sorts of different structures. Note that values will be different when using different solvent systems.
Equilibrium shifts Right & Kx > Kbenzoic Since Wx = log Kx log Kbenzoic, then W will be positive . Wx = log (Kx/Kbenzoic)
e-withdrawing groups stabilize the carboxylate ion: larger Kx, and have positive W values e.g. Cl, CN, CF3 e-donating groups (e.g. alkyl) equilibrium shifts left (favoring unprotonated): lower Kx and negative W values
Hammett Constants
Hammett constant takes into account both resonance and inductive effects; thus, the value depends on whether the substituent is para or meta substituted --ortho not measured due to steric effects In some positions only inductive effects effect & some both resonance & inductive effects play a part
Uses
Only one known example where just Hammett constants effectively predict activity (insecticides, diethyl phenyl phosphates. These drugs do not have to pass into or through a cell membrane to have activity). Log (1/C) = 2.282 W 0.348
Steric Effects
y
Examples are: y Tafts steric factor (Es) (~1956), an experimental value based on rate constants y Molar refractivity (MR)--measure of the volume occupied by an atom or group--equation includes the MW, density, and the index of refraction-y Verloop steric parameter--computer program uses bond angles, van der Waals radii, bond lengths
Hansch Analysis
Proposed that drug action could be divided into 2 stages: 1) Transport & 2) Binding Log 1/C = k1P = k2P2 + k3W + k4Es + k5
Hansch Analysis
Look at size and sign for each component of the equation. Values of r <<0.9 indicate equation not reliable Accuracy depends on using enough analogs, accuracy of data, & choice of parameters.
Craig Plots
Plots of one parameter against another. For example, T vs. W Used to quickly decide which analogs to synthesize if the Hansch equation is known.
Hansch equations
log 1/C = 1.22 T 1.59 W + 7.89 (n=22; s=0.238; r= 0.918 log 1/C = 0.398 T + 1.089 W + 1.03 Es + 4.541 (n=9; r= 0.955) log Cb = 0.765 T = 0.540 T 2 + 1.505 log 1/c = 1.78 T 0.12 W + 1.674