Monday, February 1, 2016

Istradefylline | A2A Receptor Inhibitor | Treatment for Parkinson’s Disease

Istradefylline [8-[2(E)-(3,4-Dimethoxyphenyl)vinyl]-1,3-diethyl-7-methylxanthine] is a selective adenosine A2A receptor antagonist developed as once-daily oral treatment of Parkinson’s disease (PD). Basal ganglia of the brain are recognized to play a significant role in motor control and adenosine A2A receptors are considered to be present particularly in the basal ganglia of the brain. As the abnormality observed in PD is believed to occur in the basal ganglia, it is postulated that inhibiting adenosine A2A receptor by a suitably designed inhibitor molecule could be helpful in the treatment/control of PD.

Istradefylline: E:Z ratio is 19:81 at synthesis

Istradefylline acts via a mechanism which is different from commercially available treatment options for PD which typically are dopaminergic replacement therapies, such as levodopa (a dopamine precursor) and dopamine receptor agonists. These medications have profound benefit in patients with PD, although with time, the duration of effect shortens (known as ‘wearing-off’), responses become less predictable (with rapid switching between states of mobility [ON] and immobility [OFF]), and dyskinesias and neuropsychiatric complications can develop [1].

Being a selective adenosine A2A receptor antagonist it is devoid of the adverse reactions faced by the existing agents which act on dopamine metabolism or dopamine receptors.

Istradefylline (Tradename: Nouriast) developed by Kyowa Pharmaceuticals, was approved in Japan on 25th March 2013 as an adjunctive therapy for the treatment of Parkinson’s disease (PD).

Istradefylline Synthesis

Bioorg Med Chem Lett 1997, 18(7), 2349-2352: The oldest reference for the synthesis of Istradefylline and derivatives. The yield are reported in range of 65-70%. Also see Ref. 3; same procedure, more details.

J Org Chem 2004, 69(10), 3308-3318: The authors have claimed improvement on the original synthetic route with a yield of 96%.


1H NMR (Estimated) for Istradefylline
Experimental: 1H-NMR (270MHz; CDCl3) δ (ppm): 7.74(1H, d, J=15.5Hz), 7.18(1H, dd, J=1.9, 8.3Hz), 7.08(1H, d, J=1.9Hz), 6.89(1H, d, J=8.3Hz), 6.77(1H, d, J=15.5Hz), 4.21 (2H, q, J=6.9Hz), 4.09(2H, q, J=6.9Hz), 4.06(3H, s), 3.96(3H, s), 3.93(3H, s), 1.39(3H, t, J=6.9Hz), 1.27(3H, t, J=6.9Hz). 

IR (KBr) νmax (cm-1): 1697, 1655, 1518

Sideeffects: Majority of participants from various clinical trials reported treatment-emergent adverse events (TEAEs) (79.1% with istradefylline and 75.7% with placebo), with those occurring most commonly and in greater than 4% more istradefylline than placebo recipients including dyskinesia, lightheadedness, nausea and constipation. Dyskinesia intensity was usually mild or moderate. Few istradefylline and placebo recipients reported serious TEAEs, among which were asthma, infection, urosepsis and cardiac failure with istradefylline, or discontinued therapy because of TEAEs.

1. Dungo, R.; et. al. Istradefylline: first global approval. Drugs 2013, 73(8), 875-882.
2. Shimada, J.; et. al. Adenosine A2A antagonists with potent anti-cataleptic activity. Bioorg Med Chem Lett 1997, 18(7), 2349-2352.
3. Fumio.; et. al. Therapeutic agents for parkinson's disease. EP0590919A1
4. Hockemeyer, J.; et. al. Multigram-scale syntheses, stability, and photoreactions of A2A adenosine receptor antagonists with 8-styrylxanthine structure: potential drugs for Parkinson's disease. J Org Chem 2004, 69(10), 3308-3318.