And so, the creation of
the prodrug resulted,
relatively simply, just by esterifying one
of the carboxylic acid groups resulting in
Enalapril, which had the same activity as
Enalprilat in vivo, but a thousand times less
activity in vitro. It activated, as you can
see, via biotransformation in the presence
of esterases, which in this case, were found
in the liver.
So, esterase hydrolyses off the alcohol group
from Enalapril, thus resulting in the formation
of Enalaprilat. This is the active compound
that inhibits the Angiotensin-converting enzyme,
but as I’ve just said, the Enalapril, on
its own, in vitro, doesn’t actually have anywhere
near that activity, again, demonstrating the
importance of having both carboxylic acid
groups available for interaction with the
Now, let’s talk about improving distribution.
If we go back to where we were talking about
pharmacodynamics and pharmacokinetics, we
talked about the blood brain barrier and some
of the issues associated with getting drugs
in there. In order for a drug to go through,
it needs to be a low molecular weight less
than 500 daltons and it also needs to be lipophilic
or to be able to utilise carrier proteins
in the cell membrane which exist to transport,
for example, amino acids into the cells.
If the drug itself is an amino acid, this
should directly increase the passage of a
drug across the blood brain barrier and therefore,
allow the drug to get to its site of action.
One such drug, which is a very old drug now,
but is still used is levodopa. This is an
intermediary metabolite in catecholamine synthesis.
It is decarboxylated by dopamine decarboxylate,
the results giving dopamine... giving dopamine
used in the treatment of Parkinson’s disease.
So, as a prodrug, you’ll see what I mean.
Dopamine itself is far too polar on its own
to cross the... to cross the blood brain barrier
and is therefore, not in itself, useful as
a therapeutic agent. However, levodopa is
an amino acid and crosses the blood brain
barrier via carrier proteins.
So, up on the board now, you’ll be able to
see two structures; the one on the right is
the structure for dopamine. Now, we have this
primary amine, which at physiological pH,
is going to be largely protonated. The fact
it is now largely positively charged prevents
its passive diffusion through the
blood brain barrier. This, of course, is an
issue of getting dopamine where it needs to
be in Parkinson’s disease, which is in the
And this is where levodopa comes in. Levodopa,
which is on the left hand side, as you can
see here, is, to all intents and purposes,
an amino acid, an alpha amino acid. It has
a carboxylic acid group and a primary... primary
amine attached to a central alpha carbon.
And once it cross the blood brain barrier, which
it can do via these carrier proteins which
transfer... transfer amino acids through the
blood brain... in to the blood brain barrier
though into the brain, you can get dopamine
This is facilitated by the enzyme dopa decarboxylase
and it is this activity that breaks it down
and forms dopamine which is the active compound.
So, levodopa, in this case, acts as a prodrug
in of itself, not biologically active, but
as a prodrug for decarboxylation to the active
compound dopamine, which is useful in treatment
of Parkinson’s disease, as I said before.
However, there is a problem with this and
the problem with this is that the dopa decarboxylase
activity is not the preserve of the brain.
There actually exists this enzyme in the liver,
the heart, lungs and the kidney, in fact,
there is more of it, in terms of activity
in them... than in the brain. Therefore, orally
ingested levodopa is converted to, quickly,
into dopamine in the periphery and again,
not enough of it ends up reaching the brain.
As dopamine itself cannot cross the blood
brain barrier, historically, high doses of
levodopa were needed to overcome losses in
the periphery through metabolism. However,
one way to get around this problem is by co-administering
a dopa decarboxylase inhibitor and also, sometimes
a Catechol-O-methyltransferase or COMT inhibitor
because another way in which this can be...
this can be metabolised, as you can see, is
where the oxygens or one of the oxygens of
the adjoining alcohol substituent can be methylated
by this enzyme. And so, typically, if you
are looking at a treatment with levodopa,
you’d co-administer Catechol-O-methyltransferase
inhibitor and also, a dopa decarboxylase inhibitor
to actually reduce the amount of the levodopa
which is converting to dopamine before it
actually reaches the tissue it needs to, which
is the brain.