A story of enthousiasm and failure. Some stories of drug development are worth telling. Antagonists of this receptor (A(2A) antagonists) are considered possible agents for the symptomatic treatment of PD, according to a recent reviews. In the basal ganglia many of A(2A) adenosine receptors are located, occurring mainly on the external surfaces of neurons located at striatum, globus pallidus and substantia nigra. Experimental data indicate that the best mobility improvement of patients with Parkinson's disease could be achieved with a simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A(2A) receptors. 

Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A(2A) receptors, may also have value in the management of PD and are currently explored. ^[1]  8-(-3-chlorostyryl)-caffeine (CSC), is a mixd A-2A receptors antagonist and a MAO B inhibitor. ^[2] CSC reversed behavior and biochemical alterations in a PD animal model ( 6-OHDA-lesioned rats).

Various adenosine receptor antagonists that are selective for the A(2A) receptor subtype (A(2A) antagonists) are under investigation as possible therapeutic agents for the symptomatic treatment of the motor deficits associated with PD. ^[3] (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002), is a potent A(2A) antagonist with a somehwat unfinished story to date.

Various pharmainductries are following the A2 road, such as Schering-Plough and Kyowa Hakko Kogyo ^{[4] [5][6]} First the story of a so called potent A(2A) antagonist, KW6002...

Non approvability of KW6002 

Istradefylline (KW6002) was safe, well tolerated, and offered a reduction in "off" time without increased troublesome dyskinesia in a recent trial.^[7] The magnitude in total daily awake "off" time was -1.8 +/- 2.8 hours for istradefylline and -0.6 +/- 2.7 hours for placebo (p = 0.005).  That seems interesting, but the clincial relevance is questionable... and that was also the position of the FDA.

At a low dose of levodopa, however, KW-6002 (80 mg) potentiated the antiparkinsonian response by 36% (p < 0.02), but with 45% less dyskinesia compared with that induced by optimal dose levodopa alone (p < 0.05).  All cardinal parkinsonian signs improved, especially resting tremor. Resting tremor is very difficult to treat. KW6002 has demonstrated its potential to increase motor activity in PD patients of the advanced stage in a clinical phase IIB trial. ^[8]

Based on these data, on April 25, 2007 a new drug application (NDA)was filed to the U.S. Food and Drug Administration (FDA) for Istradefylline (KW-6002).

The information given by the company was:

Phase II and III clinical studies were conducted with Istradefylline (KW- 6002) in Parkinson's disease patients experiencing "wearing-off phenomenon" on treatment with Levodopa alone or Levodopa administered concomitantly with other Parkinson's disease medications. Based on the clinical efficacy and safety data obtained, the company submitted a NDA for Istradefylline(KW-6002) as adjunctive therapy to levodopa/carbidopa for the treatment of idiopathic Parkinson's disease to improve motor function in patients who experience motor response complications. 

However,the company received on February 25, 2008 a Not approvable letter from the U.S. Food and Drug Administration (FDA) for istradefylline. In the not approvable letter FDA expressed concern if the efficacy findings support clinical utility of istradefylline (KW-6002). FDA requested an overall summary of nonclinical mineralization findings. Additionally, FDA asked for clinical pharmacology follow-up information as a Phase IV commitment.

The clinical evaluation of some other adenosine receptor ligands has meanwhile been discontinued due to: 

1. side effects due to the wide distribution of adenosine receptors,
2. low brain penetration,
3. short half-life of compounds, and
4. lack of effects, in some cases perhaps due to receptor desensitization or to low receptor density in the targeted tissue. ^[9]

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