Concert Pharmaceuticals’ precision deuteration platform can enhance metabolic properties of drugs

Substituting deuterium for certain hydrogen atoms in molecules has been shown to enhance the metabolic properties of a number of drugs and provides a promising approach to the discovery and development of innovative drug products. The deuterium chemistry approach has the potential to reduce the high failure rates of conventional drug development by building on the known pharmacology of existing compounds and leveraging their desirable therapeutic properties. Selective deuterium substitution as a means of ameliorating unwanted clinically relevant pharmacokinetic drug interactions caused by the widely-used antidepressant agent paroxetine (marketed as Paxil®) was demonstrated by researchers at Concert Pharmaceuticals and published in the July 2015, print edition of J. Pharmacol. Exp. Ther.

Deuterated compounds will generally be expected to retain the biochemical potency and selectivity of their corresponding hydrogen analogs. In select cases deuterium may impart a different metabolic profile, and the altered metabolic properties of these deuterated compounds may lead to therapeutic benefits such as improved safety, efficacy, tolerability, convenience, and reduced drug-drug interactions, as is shown in the publication. The effects, if any, of deuterium substitution on metabolic properties are highly dependent on the specific carbon positions where deuterium is substituted. Furthermore, the metabolic effects of deuterium substitution, if any, are unpredictable a priori, even in compounds that have similar chemical structures.

"This research highlights the great potential for rapidly creating best-in-class medicines with more desirable metabolic properties while reducing drug development using our Deuterated Chemical Entity Platform," stated James Cassella, Ph.D., Chief Development Officer of Concert Pharmaceuticals. "Concert has clearly shown that selective deuterium substitution can meaningfully improve the metabolic fate of drugs across a variety of important parameters."

In the published research, the two hydrogen atoms at the methylenedioxy carbon of paroxetine were substituted with deuterium using Concert's precision deuteration platform. The new chemical entity, CTP-347, demonstrated similar selectivity for the serotonin receptor, as well as similar neurotransmitter uptake inhibition in an in vitro rat synaptosome model, compared to paroxetine.

Metabolism of paroxetine creates a reactive metabolite that irreversibly inactivates the important metabolic enzyme cytochrome P450 2D6 (CYP2D6). As a result, paroxetine therapy can alter the metabolism of many other drugs that are CYP2D6 substrates, resulting in significant and undesirable alterations of their blood levels. CTP-347 produces reduced levels of the reactive metabolite, thereby helping to preserve CYP2D6 function.

CTP-347 was demonstrated to significantly reduce drug-drug interactions, relative to paroxetine, when tested with two other drugs that are metabolized by CYP2D6: tamoxifen (in vitro) and dextromethorphan (in humans). CTP-347 and paroxetine are both metabolized by CYP2D6, so CTP-347 was also clinically metabolized more rapidly and exhibited a lower pharmacokinetic accumulation index than paroxetine. CTP-347 is believed to be the first clinical compound where precision deuteration was applied to reduce drug-drug interactions without affecting its intrinsic pharmacology.