Heavyweight drugs

Non-radioactive isotopes, also known as stable isotopes, are used extensively in industry and academia. Compounds labelled with one or multiple stable isotopes (e.g. 13C, 15N, 2H, etc) combined with analytical techniques (NMR, GS, MS, IR) can provide a valuable information in the elucidation of reaction mechanisms and metabolic research.[i]

The increase in the use of deuterium labelling can be explained by the central position which hydrogen holds in chemistry and its role in proton transfer reactions. Initial studies of deuterated water, established its low toxicity towards mammalian cells.[ii] Safety is one of the benefits of stable isotopes, which enables their use for in vivo human studies.[iii] Deuteration may change the pathway of drug metabolism, which is called metabolic switching. This may lead to increased duration of action and lower toxicity.

The shape of the molecule depends on its atoms and the interactions of their electron clouds. Due to the fact that deuterated and non-labelled analogues have the same number of electrons, the shapes and sizes of the compounds are very similar (Figure 1).[iv]

Victor Fig 1 25-01-2016

Figure 1: An overlay of the crystal structures of CTP-347 hydrochloride hemihydrate (purple) and paroxetine hydrochloride hemihydrate (green)

Concert Pharmaceuticals developed a compound called CTP-347, a selectively deuterated analogue of paroxetine, for the treatment of hot flashes.[v] Modification was required, because paroxetine irreversibly inactivates the liver enzyme CYP2D6, leading to various side effects when used in combination with other medications. The proposed mechanism (Scheme 1) shows the covalent binding between paroxetine metabolite and the active site of CYP2D6, forming irreversible complex.[vi] On the contrary, CTP-347 demonstrated little to no CYP2D6 inactivation, when the experiments were performed in vitro. It is believed that selective deuteration prevents the formation of the undesired carbene metabolite.

Victor Fig 2 25-01-2016

Scheme 1: Proposed mechanism of CYP2D6 inactivation by the carbene metabolite of paroxetine

CTP-347 was subsequently studied in a patient clinical trial. Along with CTP-347, dextromethorphan was administered, which acts as a selective probe for CYP2D6 activity. Subjects receiving CTP-347 were able to metabolise dextromethorphan better than the patients who received paroxetine. This demonstrated the benefit of using deuterium over hydrogen in order to overcome undesired drug-drug interactions, potentially enabling the broader use of CTP-347 with other drugs.

Despite the change in the metabolic pathway, CTP-347 has the same inhibition and selectivity as paroxetine. In the enzyme assays the two drugs were essentially identical. Human assays proved that CTP-347 did not form any unwanted metabolites compared to paroxetine.

Additionally to the above, Auspex Pharmaceuticals announced that a deuterated version of venlafaxine causes fewer side effects and stays in the bloodstream longer than the non-deuterated version, which prolongs the action of the drug.[vii]

Although it is difficult to predict how incorporation of stable isotopes may affect the mode of a drug, it has been demonstrated experimentally that stable isotopes can provide potential improvement of the safety, tolerability, efficacy and dosing of drug candidates.

Blog written by Victor Zdorichenko

[i] Godin, J.-P.; Ross, A. B.; Rezzi, S.; Poussin, C.; Martin, F.-P.; Fuerholz, A.; Cléroux, M.; Mermoud, A.-F.; Tornier, L.; Arce Vera, F.; Pouteau, E.; Ramadan, Z.; Kochhar, S.; Fay, L.-B.; Anal. Chem. 2010, 82, 646–653

[ii] Kushner, D. J.; Baker, A.; Dunstall, T. G.; Can. J. Physiol. Pharmacol. 1999, 77, 79–88

[iii] Iglesias, J.; Sleno, L.; Volmer, D. A.; Curr. Drug Metab. 2012, 13, 1213–1225

[iv] Harbeson, S. L.; Tung, R. D.; Drug Discovery & Development magazine 2010, 13, 22

[v] Harbeson, S. L.; Tung, R. D.; In Annual Reports in Medicinal Chemistry; John E. Macor, Ed.; Academic Press, 2011; 46, 403–417

[vi] Fischer, J.; Ganellin, C. R.; Rotella, D. P.; Analogue-Based Drug Discovery III; John Wiley & Sons, 2013, 56–58

[vii] Sanderson, K.; Big Interest in Heavy Drugs. Nature News 2009


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