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Reducing Ionisation – Prodrugs

by Adam Le Gresley, PhD
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    00:00 active ingredient. Reducing ionisation.

    00:02 Now, I would like to bring you on to Angiotensin-converting Enzyme inhibitor, Enalaprilat. Enalaprilat is shown here on the right hand side. Can you work out which amino acids it contains? Hopefully, you have identified the two crucial naturally occurring amino acids here which is proline and alanine. Proline, which is the five member ring containing the nitrogen group and alanine, which is the central amino acid.

    00:34 On the left hand side, you have a species, which isn’t strictly speaking an amino acid, even though it has an alpha amino acid core, the side chain is not one which occurs naturally.

    00:44 Alanine and proline is the dicarboxylate inhibitor of angiotensin-converting enzyme which is important in hypotension regulation. Angiotensin-converting enzyme converts angiotensin 1 which is a 10 residue decapeptide into angiotensin 2 which is an octapeptide through cleaving a histidine leucine dipeptide group. Angiotensin 2, once its formed, which is the octopeptide, is a very potent vasoconstrictor which can increase blood pressure. So, with those people who have high blood pressure, it’s often useful to decrease the amount of angiotensin 2 that’s produced by the body which is usually the, if you like, first line of defence against high blood pressure. Both carboxylate groups are required for binding to the enzyme. Just go back to the structure, can you recognise those carboxylate groups? One is at the bottom there near the proline and one is on the left hand side near that benzyl side chain, which you can see, phenyl ethyl side chain. Both of those carboxylate groups are needed for binding to the enzyme and obviously, this was determined experimentally, as you will be able to see. Because the angiotensin-converting enzyme, as we have seen before, is a metalloenzyme containing a zinc ion plus an arginine residue and here, I’ve shown the ideal binding of angiotensin-converting enzyme inhibitor, an Enalaprilat, to the active side of ACE for short. Here, you can see we have a zinc ion shown as ZN2+ which is co-ordinated with the carboxylate neighbouring to the phenyl ethyl group, as we have talked about earlier. Crucially as well, the arginine residue, which is represented on the bottom right hand corner as NH3+, also co-ordinates with the carboxylates of the proline. Note in this scenario, of course, whilst arginine is a neutral species, but physiological pH it is protonated. Hence the reason why it is NH3+. This results in a strong iron ion interaction between the carboxylate to the proline and the protonated arginine NH2 group. In addition, we have hydrogen bonding donors as part of the ACE enzyme shown at the top and we also have lipophilic interactions between the benzene ring, the methyl group of the alanine central residue and also, the proline cyclopentyl ring. And if you look at this, if you look at this in detail, it was found that the compounds bearing two carboxylate groups were capable of utilising interactions with both the zinc and the arginine. This is the reason why it is such a good selective inhibitor. So, to recap, when we are looking at Enalaprilat sitting in the active side of the angiotensin-converting enzyme, we have a coordinate bond, Hydrogen bond, an ionic bond and these lipophilic binding pockets, which was low in terms of the energy of bond they have between each other, still lend themselves to that degree of selectivity that we need in order to reduce side effects. However, there is a problem. The problem is that Enalaprilat showed potent activity when given intravenously, but very poor bioavailability when given orally due to the ionisation in the gastrointestinal tract, thus limiting passive diffusion because you have those two carboxylic acid groups which effectively means that physiological pH, they are mostly going to exist as they are carboxylate conjugate base. This highly ionised system does not lend itself well to passive diffusion. What was discovered experimentally, however, was that Enalaprilat itself uses rather than passive diffusion, an intestinal carrier-mediated transporter for absorption into the intestines. What was also determined was that the ionised proline carboxylate is essential for the recognition by this transporter. However, the other carboxylic acid group is thought to prevent Enalaprilat transport... Enalaprilat transport by this route. As a consequence, modification of the carboxylate acid adjacent to the phenyl ethyl amino acid, and masking it with a group which will not ionise in the gastrointestinal tract should increase the rate of absorption via intestinal carrier-mediated transport. And so, the creation of the prodrug resulted,


    About the Lecture

    The lecture Reducing Ionisation – Prodrugs by Adam Le Gresley, PhD is from the course Medical Chemistry.


    Included Quiz Questions

    1. …a zinc atom and arginine amino acid in its active site.
    2. …an iron atom and proline amino acid in its active site.
    3. …a copper atom and proline amino acid in its active site.
    4. …a manganese atom and tyrosine amino acid in its active site.
    5. …an aluminum atom and proline amino acid in its active site.
    1. Covalent bonding between the arginine or ACE enzyme and proline of enalaprilat
    2. Strong ion-ion interaction between carboxylate of alanine and protonated NH2 of arginine
    3. Lipophilic interaction between benzene ring and methyl groups of alanine and proline of enalaprilat
    4. Hydrogen bonding in the active site
    5. Co-ordination of Zn2+ of active site with carboxylate of enalaprilat
    1. Enalaprilat gets ionized in the gastrointestinal tract when given orally; hence this leads to its poor bioavailability.
    2. Enalaprilat gets deionized in the gastrointestinal tract when given orally; hence this leads to its poor bioavailability.
    3. When given orally, enalaprilat gets degraded by gastric juices.
    4. During oral administration, the saliva enzymes react with enalaprilat to produce an allergic salt.
    5. The microbial flora of gastrointestinal tract produces enalaprilat degrading enzymes and hence makes this drug ineffective.

    Author of lecture Reducing Ionisation – Prodrugs

     Adam Le Gresley, PhD

    Adam Le Gresley, PhD


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