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 A_2A 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 A_2A 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 A_2A 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 A_2A 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 25^th 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%.

Identifications:

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) ν_max (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.

References:
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.

Drugs in Clinical Pipeline: ADX-88178

ADX-88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-1,3-thiazol-2-amine] is a small molecule positive allosteric modulator (PAM) of metabotropic glutamate receptor subtype 4 (mGluR4; GRM4). The molecule is selective for mGluR4, orally available, brain penetrant and has the potential to ameliorate Parkinsonian symptoms. Addex has reported ADX88178 as a novel mGluR4 PAM and demonstrated its efficacy in several different rodent models of Parkinson’s disease [1].

The activity of ADX88178 is as follows:

EC₅₀ (human mGluR4, FLIPR assay) = 3.5 ± 0.3 nM

EC₅₀ (rat mGluR4, FLIPR assay) = 9.1 ± 1.0 nM

K_i (human mGluR4, Binding assay) = 39 nM

Common Name: ADX-88178

Synonyms:  ADX88178; ADX 88178; ADX-88178

IUPAC Name: 5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-1,3-thiazol-2-amine

CAS Number: 1235318-89-4

SMILES: CC1=NC(=NC=C1)NC2=NC(=C(S2)C)C3=CNN=C3

Mechanism of Action: Metabotropic glutamate receptor (mGluR) modulator

Indication: Treatment for Parkinson’s disease; Treatment for PD

Development Stage: Preclinical

Company: Addex Therapeutics Ltd.

Parkinson’s disease or PD (also known as idiopathic, or primary parkinsonism, hypokinetic rigid syndrome (HRS) or paralysis agitans) is a degenerative disorder of the central nervous system mainly affecting the motor system. The motor symptoms of Parkinson’s disease result from the death of dopamine-generating cells in the substantia nigra (SN, a region in the mid brain). As a consequence of the depletion of dopamine, a series of movement disorders appear, including bradykinesia, akinesia, tremor, gait disorders and problems with balance. These motor disturbances form the hallmark of Parkinson’s disease, although there are many other non-motor symptoms also that are associated with the disease, such as sensory, sleep and emotional problems. PD is more common in older people, with most cases occurring after the age of 50. When the symptoms are observed in young adults, it is called young onset PD (YOPD). In the early course of the disease, symptoms can be effectively treated by dopamine replacement or augmentation with the use of dopamine D2 receptor agonists, such as levodopa or monoamine oxidase B inhibitors. But, as the disease progresses these agents become less effective in controlling motor symptoms. Also, the use of these agents is limited by the emergence of adverse effects including dopamine agonist-induced dyskinesias. Therefore, activation of metabotropic glutamate receptor 4 (mGluR4) has been proposed as a potential therapeutic approach to treat Parkinson’s disease [2, 3, 4].

The metabotropic glutamate receptor 4 (mGlu4) belongs to the Group III mGluRs (Class C G-Protein Coupled Receptor) and is negatively coupled to adenylate cyclase via activation of the Gai/o protein. It is expressed primarily on presynaptic terminals, functioning as an autoreceptor or heteroceptor and its activation leads to decreases in transmitter release from presynaptic terminals. MGlu4 is currently receiving much attention based primarily upon its unique distribution in key brain region involved in many CNS disorders. MGlu4 PAM is emerging as a promising target for the treatment of motor and non-motor symptoms as well as a disease-modifying agent in Parkinson`s disease through a non-dopaminergic approach.

Symptoms of Parkinson’s disease are believed to be due to progressive death of dopaminergic. Reduction in dopaminergic neurotransmission leads to an imbalance in the direct and indirect output pathways of the basal ganglia. Reduction of transmission at the inhibitory GABAergic striato-pallidal synapse in the indirect pathway is believed to result in alleviation of these symptoms. mGluR4 is abundant in striato-pallidal synapses. Its localization suggests it functions as a presynaptic heteroreceptor on GABAergic neurons, suggesting in turn that selective activation or positive modulation of mGluR4 would decrease GABA release in this synapse, thereby decreasing output of the indirect pathway and reducing or eliminating the PD symptoms.

In vitro properties of ADX88178 were evaluated by monitoring calcium mobilization in HEK293 cell lines modified to express human and rat mGluR4. ADX88178 was also evaluated in a radioligand binding assay with human mGluR4 receptors obtained from membranes from the HEK293 cell line. The compound completely displaced the specific binding of [³H]PAM2, a structurally distinct compound in this assay. When investigated for its selectivity for mGluR4, ADX88178 exhibited no effect on mGluR1, 2, 3, 5, 7 or GABA_B at concentrations upto 30 uM. Agonist activity at mGluR6 was detected with an EC₅₀ value greater than10 uM, while the compound acted as a PAM at mGluR8 with an EC₅₀ of 2.2 uM. The compound was found to be inactive at 10 uM when screened against other receptors, transporters, enzymes and ion channels in the Cerep panel, except human adenosine A1 and A3 [1].

ADX88178 reverses haloperidol induced catalepsy (HIC) in rats at 3 and 10 mg/kg after oral administration. More importantly, the combination of ADX88178 (3, 10 and 30 mg/Kg, p.o.) with a low dose of L-DOPA enabled a robust, dose-dependent reversal of the forelimb akinesia deficit induced to a bilateral 6-OHDA lesion of the striatum in rats. In addition, co-administration of ADX88178 (10 mg/kg, p.o.) did not worsen dyskinesia induced by L-DOPA in rats subjected to a unilateral 6-OHDA lesion of the medial forebrain bundle. This is consistent with an L-DOPA sparing action that may prove to be therapeutically useful for the management of motor symptoms of PD.

References:

1. Le Poul, E.; et. al. A potent and selective metabotropic glutamate receptor 4 positive allosteric modulator improves movement in rodent models of Parkinson’s disease. J Pharmacol Exp Ther 2012, 43(1), 167-177.

2. Marino, M. J.; et. al. Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson’s disease treatment. Proc Natl Acad Sci USA 2003, 100(23), 13668-13673.

3. Marino, M. J.; et. al. Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors. Curr Opin Pharmacol 2006, 6(1), 98-102.

4. Duty, S. Therapeutic potential of targeting group III metabotropic glutamate receptors in the treatment of Parkinson’s disease. Br J Pharmacol 2010, 161(2), 271-287.

Tolcapone

Common name: Tolcapone; Ro-40-7592; Tasmar
Trademarks: Tasmar
Molecular Formula: C14H11NO5
CAS Registry Number: 134308-13-7
CAS Name: (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone
Molecular Weight: 273.241
SMILES: CC1=CC=C(C=C1)C(=O)C1=CC(=C(O)C(O)=C1)[N+]([O-])=O
InChI Key: MIQPIUSUKVNLNT-UHFFFAOYSA-N
InChI: InChI=1S/C14H11NO5/c1-8-2-4-9(5-3-8)13(17)10-6-11(15(19)20)14(18)12(16)7-10/h2-7,16,18H,1H3
Activity:  Treatment of Parkinson's Disease; COMT Inhibitors; Antiparkinsonian Drugs
Status: Launched 1997; Withdrawn 1998; Re-launched 2009
Originator: Chugai; Roche/Bristol-Myers Squibb

Tolcapone synthesis: Helv Chim Acta 1989, 72, 952-968 (Also Ref. 2, 3)

Raw Materials:

Lithium; 4-Benzyloxy-3-methoxybenzaldehyde; 4-Bromotoluene; Hydrogen bromide; Nitric acid

Procedure: 

Step a: 143.8 ml of n-butyllithium solution (1.53M in hexane) are added dropwise at -70° within 30 minutes to 35.0 g of 4-bromotoluene (dissolved in 600 ml of tetrahydrofuran), After stirring at -70° for 60 minutes 48.5 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 450 ml of tetrahydrofuran) are added dropwise thereto during 30 minutes. The reaction mixture is stirred at -70° for 2 hours and at 0° for 30 minutes, poured into a mixture of ice and 150 ml of 2N sulfuric acid and extracted three times with 500 ml of ether. The combined ether phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. There is obtained 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol as a yellowish oil which can be used directly in the subsequent reaction step.

Step b: 69.8 g of 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol (dissolved in 600 ml of methylene chloride) are treated within 30 minutes at 20° with 45.3 g of pyridinium chlorochromate and stirred at 20° for 3 hours. The precipitate formed is subsequently filtered and washed with methylene chloride. The filtrate is evaporated and the residue is filtered on 100 g of silica gel with ether. After recrystallization from ether, there is obtained 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone.

Step c: 170 ml of 33 percent hydrobromic acid in glacial acetic acid are added at 20°-25° within 20 minutes to 42.4 g of 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone (dissolved in 450 ml of methylene chloride). After stirring at 20° for 1.5 hours, the reaction mixture is poured into 750 ml of ice-water; the methylene chloride phase is separated and the aqueous phase is extracted twice more with 200 ml of methylene chloride. The combined methylene chloride phases are washed with 1200 ml of water, dried over sodium sulfate and evaporated. In order to remove the resulting benzyl bromide, the oily residue is treated with hexane and decanted off. There is obtained 4-hydroxy-3-methoxy-4'-methylbenzophenone as a yellowish oil which can be used directly in the subsequent reaction step.

Step d: 7.8 ml of 65 percent nitric acid are added dropwise at 20° within 20 minutes to 29.4 g of 4-hydroxy-3-methoxy-4'-methylbenzophenone (dissolved in 450 ml of acetic acid). After stirring for 1.5 hours, the reaction mixture is poured into 2 l of ice-water and the precipitate formed is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from methanol. There is obtained 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzo-phenone of m.p. 137°-139° (from methylene chloride/ether).

Step e: 24.8 g of 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzo-phenone (dissolved in 120 ml of glacial acetic acid, 100 ml of 33 percent hydrobromic acid in glacial acetic acid and 68 ml of 48 percent aqueous hydrobromic acid) are boiled under reflux for 4 hours. The reaction mixture is subsequently evaporated under reduced pressure and the residue is distilled with toluene. The residue is dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated. The product is crystallized from methylene chloride/low-boiling petroleum ether. There is obtained  3,4-dihydroxy-4'-methyl-5-nitrobenzophenone  (Tolcapone, Ro 40-7592) of m.p. 146°-148° (from methylene chloride).

Side-effect: TASMAR (tolcapone) should ordinarily be used in patients with Parkinson's disease on L-dopa/carbidopa who are experiencing symptom fluctuations and are not responding satisfactorily to or are not appropriate candidates for other adjunctive therapies. TASMAR should be discontinued if SGPT/ALT or SGOT/AST levels exceed 2 times the upper limit of normal or if clinical signs and symptoms suggest the onset of hepatic dysfunction (persistent nausea, fatigue, lethargy, anorexia, jaundice, dark urine, pruritus, and right upper quadrant tenderness).

References:
1. Borgulya, J.; et. al. Catechol-O-methyltransferase-inhibiting pyrocatechol derivatives: Synthesis and structure-activity studies. Helv Chim Acta 1989, 72, 952-968.
2. Bernauer, K.; et. al. Catechol derivatives. US5476875
3. Bernauer, K.; et. al. 3,5-Disubstituierte Pyrocatecholderivate. EP0237929B1