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Copyright © Huntington Study Group 2014. All rights reserved. Deuteration, the selective substitution of deuterium for hydrogen in compounds that have known biological effects, can slow metabolism of these compounds by decreasing the rate of chemical reactions required to break down the compound, an effect known as the deuterium isotope effect. 4 Deuteration has been explored since the 1960s as a way to potentially decrease toxicity of drug metabolites and extend biological half-life. 2,4-8 As evidenced by the failure of several deuterated compounds prepared to date, deuteration can result in unexpected metabolic changes that render some deuterated compounds more toxic or less effective than their non-deuterated analogs (Table 1). However, several pharmaceutical firms have recently begun trials with promising new deuterated formulations, including Auspex Pharmaceuticals' deuterated analog of tetrabenazine (SD-809) for use in individuals with HD and other hyperkinetic movement disorders. Preliminarily, SD-809 shows similar efficacy to tetrabenazine at lower doses and with a longer duration of action. 3 Clinical trials of SD-809 in HD are currently underway. 9,10 A Brief History of Deuterated Pharmaceuticals By: Meredith Achey, BM Table 1. Selected deuterated compounds and their indications. Base compound Deuterated analog Indication Developer Timeline Results Morphine[11] n/a Analgesia UC Berkeley 1961 Unsuccessful: deuteration slowed formation of active metabolite. Tramadol[12] n/a Analgesia Sepracor 2006 Unsuccessful: deuteration slowed formation of undesirable metabolites, but failed to extend drug duration of action. Fludalanine[4] n/a Antibiotic Merck 2008 Trials halted in Phase 2b, due to buildup of fluorolactate in patients. Venlafaxine[2,4] SD-254 Neuropathic pain Auspex Pipeline Results of phase 1 trials indicate increased drug exposure and decreased metabolic variability. Tetrabenazine[3] SD-809 Hyperkinetic movement disorders Auspex Pipeline Currently in phase 3 trials for HD. Trials planned for tardive dyskinesia and tics in Tourette syndrome. Paroxetine[2,4] CTP-347 Hot flashes Concert Pipeline Results of phase 1 trials show potential for decreased negative interactions. Atazanavir[2,4] CTP-518 HIV Concert Pipeline Currently under investigation for treatment of HIV without concomitant Ritonavir. 1 Paleacu D. Tetrabenazine in the treatment of Huntington's disease. Neuropsychiatr Dis Treat. 2007 October; 3(5):545–551. 2 Tung R. The development of deuterium-containing drugs. Concert Pharmaceuticals. www.concertpharma.com/news/ documents/IPT32ConcertPharma.pdf Accessed Dec 30, 2013. 3 Stamler DA, Brown F, Bradbury M. The pharmacokinetics of extended release SD-809, a deuterium-substituted analogue of tetrabenazine [abstract]. Mov Disord. 2013;28 Suppl 1 :765 4 Harbeson SL, Tung RD. Deuterated drugs as clinical agents. Annu Rep Med Chem. 2011 Oct. 12;46:412-414. 5 Yarnell AT. Heavy-hydrogen drugs turn heads, again. C&EN 2009;87(25):36-39. 6 Blake MI, Crespi HL, Katz JJ. Studies with deuterated drugs. J Pharm Sci. 1975;64:367–391. doi: 10.1002/jps.2600640306 7 Kushner DJ, Baker A, Dunstall TG. Pharmacological uses and perspectives of heavy water and deuterated compounds. Can J Physiol Pharmacol. 1999 Feb;77(2):79-88. 8 Sanderson K. Big interest in heavy drugs. Nature. 2009 Mar 19;458(7236):269. 9 First time use of SD-809 in Huntington disease (First-HD). ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/ NCT01795859. Accessed Dec. 2, 2013. 10 Long term safety study of SD-809 in patients chorea associated with Huntington disease (ARC-HD). ClinicalTrials.gov. http:// clinicaltrials.gov/ct2/show/NCT01897896. Accessed Dec. 2, 2013. 11 Elison C, Rapoport H, Laursen R, Elliott HW. Effect of deuteration of N-CH3 group on potency and enzymatic N- demethylation of morphine. Science. 1961 Oct 13;134(3485): 1078-9. 12 Shao L, Abolin C, Hewitt MC, Koch P, Varney M. Derivatives of tramadol for increased duration of effect. Bioorg Med Chem Lett. 2006 Feb;16(3):691-4. Epub 2005 Oct 27. H D I N S I G H T S HD Insights, Vol. 7 4