Meet the Compound: SD-809 (dutetrabenazine)

Image source: Auspex Pharmaceuticals, Inc. United States Securities and Exchange Commission Form S-1: Registration Statement. Filed December 20, 2013. www.nasdaq.com/markets/ipos/filing.ashx?filingid=9241956 . Accessed January 21, 2014.

Image source: Auspex Pharmaceuticals, Inc. United States Securities and Exchange Commission Form S-1:
Registration Statement. Filed December 20, 2013. www.nasdaq.com/markets/ipos/filing.ashx?filingid=9241956 . Accessed January 21, 2014.

Molecular Formula: C19H21D6NO

Molecular Weight: 324 g/mol

Mechanism of Action: Tetrabenazine reversibly inhibits monoamine re-uptake, which depletes monoamines and reduces involuntary movements.1 Auspex Pharmaceuticals, developer of SD-809, has shown that deuteration of tetrabenazine may slow its metabolism and decrease the need for large repeated doses.2,3


A Brief History of Deuterated Pharmaceuticals

By: Meredith Achey, BM

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

table


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 Ndemethylation 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; 1 6(3):691-4. Epub 2005 Oct 27.