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Med Chem notes

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11 views21 pages

App A

Med Chem notes

Uploaded by

Joe Black
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© © All Rights Reserved
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• It is possible to derive from the Henderson‐

Hasselbalch equation an expressions for the


variation in the partitioning of organic acids and
bases into organic solvent with respect to the pH
of the solution that they are dissolved in.

– P: is a constant because it refers to the partition


coefficient of only the UNIONISED form
– Papp: is the apparent partition coefficient, which varies
with pH.
– Papp can predict the behaviour of a compound at all
pH values as long as we know P and pKa.
160
Papp of acids:

– At pH values below the pKa; Papp = P,


– Because ionisation is suppressed and we are dealing
with only the unionized form of the species.
– At pH values above the pKa the value of Papp decreases
because the species is ionizing and moving into the
aqueous layer.
• This relationship is very simple and allows us to
predict the distribution at all pH values, provided
that we know pKa and log P, for any given
compound.

161
Papp of bases:

– At pH values well above pKa, the base exists


almost completely in the non‐ionised form and we
find that Papp = P.
– At pH values below pKa, increasing acidity tends to
protonate the amine in the aqueous layer,
reducing the conc.
• When a compound, acid or base, is 50%
ionised (i.e. pH = pKa) its partition coefficient
is half that of the drug in the unionised state.
P P
Papp = =
1 + 100 2 162
2.3. Lipinski’s Rule of Five

Orally active drugs generally show a balance of


hydrophilic/hydrophobic properties and obey at least three of
the following rules:

• MW < 500
• No more than 5 HBD groups
• No more than 10 HBA groups
• log P < +5

Not foolproof - several exceptions


Lipinski’s ‘rules’ are really guidelines

163
Exceptions

• Small polar molecules (MW <200) that cross the gut wall
through small pores between cells
• Polar molecules carried across the membrane by transport
proteins - amino acids, nucleic acid bases and some drugs (e.g.
lisinopril)
NH2

HO N
N
H
O O CO2H

164
Drug

Cell
Membrane
Cell Transport
RECEPTOR
Protein
Membrane

Cell

165
Cell
Membrane
Cell Transport
RECEPTOR
Protein
Membrane

Cell

166
Exceptions
Pinocytosis - a process allowing passage of large polar drugs
into a cell without actually crossing the cell membrane

Drug released
into cell

Drug Pinocytosis
Drug passed
through cell

167
Veber’s parameters

• Molecular flexibity is important to drug absorption


• Too many rotatable bonds is bad for absorption
• The polar surface of the molecule plays a role
• Molecular weight is not a factor

Total no. of HBDs and HBAs ≤ 12


Number of rotatable bonds ≤ 10

or

Polar surface area < 140 Angstroms


Number of rotatable bonds ≤ 10

168
2.4. SOLUBILITY AND THE STRUCTURE OF DRUG

• The structure of a compound will influence its solubility in water and


lipids.

• Water solubility will depend on:

- The number and nature of the polar groups in its structure.

*Polar groups that ionize in water will usually result in a higher


water solubility than those that do not ionize.

- The size and nature of the compound’s carbon–hydrogen skeleton.

*Aromatic compounds do tend to be less soluble in water than


the corresponding non aromatic compounds.
169
• The water solubility of a lead compound can be improved by two
general methods:
a. Salt formation
b. Incorporating water solubilizing groups into its structure

a. Salt formation:

• Salts of drugs dissociate in water to produce hydrated ions.

•The degree of water solubility of a salt will depend on the structure of


the acid or base used to form the salt

170
• Salts of low water solubility can be used as a
drug depot.
– Penicillin G procaine has low solubility in water.
• When administered as a suspension by intramuscular
injection it acts as a depot by slowly releasing penicillin.
– Low solubility used to change the taste of drugs to
make them more palatable to the patient.
• The antipsychotic chlorpromazine hydrochloride has a very
bitter taste
• The water‐insoluble embonate salt is almost tasteless and
can be administered orally in the form of a suspension.

171
b. The incorporation of water solubilizing groups to drug structure

• Incorporation of polar groups into the structure of a compound


-This will result in the formation of an analogue with a better
water solubility.

• The incorporation of strongly polar will enhance water solubility:


- alcohol, amine, amide, carboxylic acid, sulphonic acid

• Water solubilizing groups are best introduced at the beginning of a


drug synthesis
-They may be introduced at any stage.
-To avoids the problem of changing the type and nature of the
drug–receptor interaction.

172
A. Introducing carboxylic acid groups
– By Alkylation of alcohols, phenols and amines
with suitably substituted acid derivatives.
• O‐alkylation of alcohols and phenol
• N‐alkylation for amines is used to introduce carboxylic
acid

173
– Acylation of alcohols, phenols and amines with
the anhydride of the appropriate dicarboxylic acid.

174
B. Introducing Sulphonic acid groups:
– Sulphonic acid groups can be incorporated into
the structures by direct sulphonation with
concentrated sulphuric acid

175
C. Introducing a basic groups

176
D. Polyhydroxylation:
• The introduction of polyhydroxy chains is used to
improve water solubility,
• Hydroxyethoxy and dihydroxy residues have been
introduced by:
– Reaction of the corresponding monochlorinated hydrin
– Also by using a suitable epoxides

177
Improving lipid solubility
• The commonest way to improve lipid solubility is:
– To introduce non‐polar groups into the structure
– Or replace polar groups by less polar groups.
• Methyl, fluoro and chloro groups are commonly used
for this purpose.

178
3. DRUG DISTRIBUTION
• Once across the gut wall, the drug enters blood vessels, cells lining
the blood vessels are loose fitting. No need for the drug to cross cell
membranes

• Drug can quickly cross blood vessel walls through pores between the
cells

• Drugs absorbed orally are first taken to the liver, modification of the
drug is possible by enzymes in the liver - drug metabolism

• A certain percentage of the absorbed drug is often deactivated by


drug metabolism in the liver before distribution occurs round the body
- first pass effect

• Drug is distributed evenly throughout the blood supply within 1 min


of absorption. 179
• Uneven distribution round body due to uneven blood supply

• Rapid distribution from blood vessels to tissues and organs

• Drug be effective if its target site is a receptor situated in a cell


membrane or has to enter a cell if target is within the cell

• Blood concentration drops rapidly after absorption due to


distribution, macromolecular binding such as albumin so lower the
level of free drug, and storage in fat tissue (e.g. barbiturates) so it is
difficult to estimate the safe dosage.

• Blood brain barrier hinders polar drugs from entering brain


-tight fitting cells line the capillaries in the brain
-capillaries have a coating of fat cells

• Can increase polarity of peripherally acting drugs to reduce CNS


side effects 180

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