Deuterium, a hydrogen atom with an extra neutron in the nucleus, has the property of forming stronger bonds with other atoms. It turns out that by replacing hydrogen atoms with deuterium in drug molecules, it is possible to improve the pharmacodynamic and even pharmacokinetic profiles of some drugs.
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The field of pharmacologic deuteration is so promising that new companies are springing up, ready to convert already successful meds into deuterated drugs. Take for example Auspex Pharmaceuticals, a Vista, CA startup. The company reports that it has close to 50 drug candidates in its pipeline, including propanolol, simvastatin, and azythromycin. (Here”s a compelete list of product candidates from Auspex.)
The other company developing deuterated compounds is Concert Pharmaceuticals, Inc. from Lexington, Mass., which just announced positive results from Phase I clinical study of its CTP-347 drug, “an investigational non-hormonal treatment for vasomotor symptoms (hot flashes).” It turns out that CTP-347 is none other than a Prozac (Paroxetine) version ready to be deployed in thermonuclear weapons, thanks to its 2H modification of the Paroxetine molecule.
Here’s what Concert Pharmaceuticals says about the results of the trial:
CTP-347, a novel deuterium-modified analog of paroxetine discovered at Concert, was well-tolerated at all doses. Paroxetine is a serotonin reuptake inhibitor that has been shown to reduce vasomotor symptoms. However, paroxetine inactivates the important liver enzyme CYP2D6 which can lead to serious side effects when used in combination with many common medications. In contrast, in this study, CTP-347 substantially retained the activity of this key enzyme, potentially enabling its broader use with other drugs. These clinical results confirm Concert’s preclinical observations. The Company expects to present the complete Phase 1 results at a future medical meeting in 2009.
“After our encouraging preclinical findings with CTP-347, we were pleased to see a consistent deuterium effect in a clinical setting,” stated Roger Tung, Ph.D., President and Chief Executive Officer of Concert Pharmaceuticals. “In preclinical studies, Concert has shown that selective deuterium substitution can improve the metabolic fate of drugs across a variety of parameters. This study addresses one important parameter and supports our belief that deuterium technology has great potential for rapidly creating best-in-class medicines with reduced risk.”
The Phase 1 clinical trial was a randomized, single-blind, placebo-controlled, ascending single- and multiple-dose study in 94 healthy volunteers. The primary objective of the study was to evaluate the safety, tolerability and pharmacokinetics of CTP-347. In this trial, CTP-347 was well-tolerated at all doses evaluated; there were no clinically significant adverse events reported and the pharmacokinetics were consistent with those observed in preclinical studies.
As part of the multi-dose phase of the study, the extent to which CTP-347 inhibits the drug-metabolizing enzyme, CYP2D6, was evaluated by co-dosing subjects with dextromethorphan, which is metabolized by CYP2D6. In this portion of the study, women dosed with CTP-347 substantially retained their ability to metabolize dextromethorphan, suggesting that time-dependent inactivation of CYP2D6 was not observed with CTP-347 and indicating that CTP-347 may have a reduced potential for drug-drug interactions.