COMPOUNDS FOR USE IN THE TREATMENT OF ADCY5-RELATED DYSKINESIA

Abstract

The present invention relates to compounds and compositions comprising said compounds, for use in the treatment of ADCY5-related dyskinesia.

Claims

1. A method for treating ADCY5-related dyskinesia, comprising administering to a patient in need thereof a composition comprising at least a compound of formula (I): ##STR00004## wherein: R.sub.1 is selected from H, CH.sub.3 and C.sub.2H.sub.5, R.sub.2 is selected from H, CH.sub.3 and C.sub.2H.sub.5, R.sub.3 is selected from H, CH.sub.3 and C.sub.2H.sub.5, R.sub.4 is selected from H, CH.sub.3, C.sub.2H.sub.5 and ##STR00005## or pharmaceutically acceptable salts thereof; and at least one pharmaceutically acceptable excipient.

2. The method according to claim 1, wherein said compound is selected from the group consisting of: ##STR00006## and pharmaceutically acceptable salts thereof.

3. The method according to claim 1, wherein said compound is caffeine or a pharmaceutically acceptable salt thereof.

4. (canceled)

5. The method according to claim 1, wherein said composition is administered by enteral route, in particular by oral or rectal administration, or by parenteral route, in particular by injection.

6. The method according to claim 1, wherein said composition is in the form of a beverage, a food, a pill, a tablet, a syrup, a patch, a gum, a powder, a capsule or a vial.

7. The method according to claim 1, wherein said composition is in the form of a beverage or a food comprising or consisting of coffee beans, tea leaves, cocoa nuts, kola nuts, guarana seeds and yerba mate leaves.

8. The method according to claim 1, wherein said composition is formulated into unit dose forms from 10 to 1 000 mg, from 50 to 500 mg, from 100 to 300 mg or from 10 to 100 mg of said compound.

9. The method according to claim 1, wherein said composition is formulated into unit dose forms of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1 000 mg of said compound.

10. The method according to claim 1, wherein said composition is administered one or more times per day.

11. The method according to claim 1, wherein said composition is administered once daily, twice daily, three times daily or four times daily.

12. The method according to claim 3, wherein the composition comprising caffeine is administered three times daily with an uptake of 100 mg of caffeine in the morning, an uptake of 100 mg in the afternoon and an uptake of 50 mg at bedtime, preferably in the form of a coffee drink.

13. The method according to claim 3, wherein the composition comprising caffeine is administered four times daily with an uptake of 100 mg of caffeine in the morning, an uptake of 100 mg in the afternoon, an uptake of 100 mg at bedtime and an uptake of 100 mg at night, preferably in the form of a coffee drink.

Description

EXAMPLES

Example 1

[0051] Two patients, a father and a daughter, were diagnosed by the Inventors as suffering from ADCY5-related dyskinesia. They had diurnal and nocturnal paroxysmal dyskinesia as well as a mild permanent movement disorder. They had self-medicated for years with coffee, which they said could prevent the occurrence of episodes. According to the father, he would never go to bed without drinking coffee, or else he would be woken up by dyskinesia. The below experiments were carried out to report in detail the efficacy of caffeine in another patient with ADCY5-related dyskinesia and discuss the rationale supporting caffeine use in this condition.

[0052] The patient is an 11-year-old boy with the disorder. Pregnancy, birth and first acquisitions were unremarkable. At the age of three, he developed diurnal and nocturnal episodes of hyperkinetic involuntary movements involving the face and upper limbs, lasting from a few seconds to ten minutes. There was a clear kinesigenic trigger for some of the episodes, others were exercise-induced, and a few were spontaneous. In addition, he was described as clumsy, and had difficulties in various activities of daily living such as fine motor tasks or riding a bike. Frequency of the episodes was around 30 per day at age 11, causing significant disruption of activities. For example, he had trouble writing in class, was not able to walk home from school and could not do sports. Interictal neurological examination was normal except for some fleeting choreodystonic movements. Because of the co-occurrence of several types of paroxysmal dyskinesia, the patient was first tested for mutations in the SLC2A1 and ADCY5 genes. Genetic analysis was negative for SLC2A1 but found a mosaic heterozygous mutation in the ADCY5 gene (c.2088+1G>A), previously reported as pathogenic (Carapito et al., A de novo ADCY5 mutation causes early-onset autosomal dominant chorea and dystonia. Mov Disord. 2015; 30(3):423-7).

[0053] Caffeine was the first treatment tried. The parents were not surprised by the coffee prescription, as it is a commonly used medicine for various ailments in both children and adults in Madagascar, their country of origin. He was first started on one espresso in the morning, approximately 100 mg of caffeine, with a dramatic response starting 45 minutes after intake and lasting for seven hours. He then took a second espresso in the afternoon and half an espresso at bedtime, with next to complete resolution of the diurnal and nocturnal episodes. There were at most one or two short and non-disruptive episodes during the day. The patient was able to resume regular activities such as writing in class or walking home from school, and even started riding a bike again.

[0054] In a fortuitous, real-life double-blind experiment, the parents unknowingly bought decaffeinated coffee, resulting in immediate reversal to baseline for four days until the mistake was discovered. Caffeine intake immediately restored the improvement noted before.

[0055] ADCY5-related dyskinesia is believed to be due to gain of function mutations of adenylate cyclase type 5, which is mainly expressed in the striatum. In the striato-pallidal neurons, adenylate cyclase type 5 is inhibited by dopamine through D2 receptors and activated by adenosine through A.sub.2A receptors (A.sub.2AR), whose density is high in the striatum. Antagonizing A.sub.2AR and thereby inhibiting adenylate cyclase type 5 therefore makes sense in order to reduce the hyperkinetic movement disorder seen in patients with ADCY5-related dyskinesia. Caffeine is the most commonly consumed drug in the world and is an antagonist of adenosine receptors. It probably acts primarily through A.sub.2AR, as its wake-promoting effect is abolished in A.sub.2AR knockout mice (Huang et al., Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci. 2005; 8(7):858-9.). In light of this strong rationale and clinical experience of the Inventors, caffeine and analogous compounds antagonists of adenosine receptors 2A appear to be effective and promising treatments in patients with ADCY5-related dyskinesia.

Example 2

[0056] Currently, seven patients are treated with caffeine with similar results with uptakes varying from 150 to 800 mg of caffeine per day. In all cases, it is observed a reduction or a suppression of dyskinesia episodes. Four of them were asked to rate the improvement brought by caffeine on their involuntary movements, on a scale of 0 (no improvement) to 100% (major improvement with total disappearance of symptoms). All four reported an improvement of 80 to 100%.