Monday, May 2, 2016

Perampanel | AMPA Receptor Antagonist I Antiepileptic Drug I Treatment for Seizures

Perampanel [2-(6'-oxo-1'-phenyl-1',6'-dihydro-[2,3'-bipyridin]-5'-yl)benzonitrile] is an orally-active, selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist. Perampanel is developed as a novel antiepileptic drug (AED) to be used as adjunctive therapy in adolescents and adults with partial-onset seizures (with or without secondarily generalized seizures).
It comes with two firsts: (a), first in this new class of AED known as AMPA receptor antagonists, (b)  first-in-class AED drug offering the convenience of once-daily administration [1, 2].

Perampanel: 2D and 3D Structure

Briefly, AMPA receptors are ligand-gated ion channels activated by glutamate, the major excitatory neurotransmitter in the CNS, which is thought to have an important role in inducing seizures. Although there are other ionotropic glutamate receptors in the CNS (N-methyl-D-aspartate, kainate), AMPA receptors appear to be the predominant mediator of excitatory neurotransmission and are involved in the generation and spread of seizure activity. 

Perampanel has been approved in the EU and in the USA as adjunctive treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older.

Glutamate Receptors in Brain as Targets for Therapy
The amino acid glutamate is the primary excitatory neurotransmitter in the human brain. In the case of epilepsy, it is more than 5 decades since an increase of glutamate concentrations in the brain above a critical level was proposed to be the trigger for seizure activity. Moreover, dysfunction of glutamatergic neurotransmission has long been implicated in the pathogenesis of many other neurological diseases including Parkinson’s disease, neuropathic pain, and stroke, etc.
Glutamate exerts its physiologic effects via interaction with two major families of receptor proteins: metabotropic glutamate receptors (mGluRs) and ionotropic glutamate receptors (iGluRs). mGluRs allow glutamate to modulate cell excitability and synaptic transmission via second messenger signaling pathways, while iGluRs are ligand-gated tetrameric ion channels that mediate fast synaptic responses to glutamate.
Three classes of iGluRs have been identified and are named according to their selective agonists: AMPA, kainate, and NMDA. Moreover, the discovery and characterization of mGluRs and iGluRs led to intensive efforts over the past 2 decades to generate novel drugs that inhibit the activity of these receptors. Nevertheless, no specific glutamate receptor antagonists have been approved for clinical use [3].

Perampanel as an AMPA Receptor Antagonist
Perampanel with the unique 1,3,5-triaryl-1H-pyridine-2-one structure led to good drug metabolism and pharmacokinetic properties, overcoming the weaknesses of some earlier AMPA receptor antagonists.
In pharmacological studies, Perampanel had potent inhibitory effects both in vitro and in vivo (AMPA-induced Ca2+ influx assay: IC50 of 60 nM; AMPA-induced seizure model: minimum effective dose (MED) of 2 mg kg-1 po) [3].
In addition, binding assay results indicated that perampanel has a similar binding site to other noncompetitive AMPA receptor antagonists. From radioligand binding assays, which included 63 physiologically relevant enzymes, and neurotransmitter transporters, perampanel was also found to be highly selective for the AMPA receptor.

Studies in rat cortical neurons have shown potency for Perampanel, with an IC50 of 93 nM for inhibiting AMPA-evoked calcium currents. In comparison GYKI52466, another noncompetitive AMPA receptor antagonist had an IC50 of 12.5 uM.

Perampanel’s selectivity for AMPA receptors over other receptors has been shown in rat hippocampal studies, where Perampanel reduced AMPA receptor-mediated excitatory postsynaptic field potentials with an IC50 of 0.23 uM and a full block at 3 uM. By contrast, 10 uM Perampanel had no effect on responses mediated by N-methyl-D-aspartate (NMDA) or kainate receptors, which were completely blocked by the NMDA receptor blocker D-AP5 (30 uM) and the AMPA and kainate receptor blocker NBQX (10 uM).

Dosages and Approvals:
Perampanel (Tradename: Fycompa) is approved in the EU (2012) and in the USA (2012) for the adjunctive treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older.  Fycompa should be taken once daily before bedtime; start with a dose of 2 mg/day; the dose may be increased based on clinical response and tolerability by an increment of 2 mg/day to a dose of 4 mg to 12 mg/day. The maximum recommended daily dose is 12 mg once daily. Dose increases should occur at weekly intervals and no more frequently than that.
Some aspects of dosage and administration recommendations vary between the EU and the USA, and local prescribing information should be consulted.
Perampanel is not recommended in patients with moderate or severe renal impairment, including those on haemodialysis. In both the EU and the USA, perampanel is not recommended in patients with severe hepatic impairment. In case of mild renal/hepatic impairment lower dosages, mainly 4 mg of Perampanel is allowed. 

Perampanel Synthesis

J Med Chem 2012, 55(23), 10584-10600: This is an earlier reported synthetic route. Many other potent derivatives too are reported.

US20070142640A1: The patent reports various permutations and combinations of raw materials, catalysts and conditions to synthesize Perampanel is quantitative amounts. The reported procedure is one that provides maximum yield; and could be a choice for industrial production.


1H NMR (Estimated) for Perampanel

Experimental: 1H NMR (400 MHz, DMSO-d6) δ 7.31 (dd, J = 4.8, 7.6 Hz, 1H), 7.48-7.63 (m, 6H), 7.73 (dd, J = 8.4 Hz, 1H), 7.79 (ddd, J = 1.2, 6.4, 8.0 Hz, 1H), 7.85 (ddd, J = 2.0, 6.4, 8.0 Hz, 1H), 7.94 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 2.8 Hz, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.59 (ddd, J = 0.8, 1.2, 4.8 Hz, 1H).
13C NMR (Estimated) for Perampanel
Experimental: 13C NMR (150 MHz, CDCl3) δ 112.5, 118.3, 118.6, 118.8, 122.1, 126.7 2*C, 128.2, 128.8, 129.0, 129.4 2*C, 131.1, 132.3, 133.2, 137.1, 138.0, 138.9, 140.3, 140.9, 149.8, 153.1, 160.5.

Sideeffects: The four most common treatment-emergent adverse events (TEAEs) considered to be adverse drug reactions (ADRs) were dizziness, somnolence, fatigue and irritability; most of these events occurred during initial titration. Other common ADRs included nausea and falls. Of note, dizziness, fatigue and fall, occurred at a numerically higher rate in elderly (n = 20) versus adult (n = 920) perampanel-treated patients. The most common TEAE not considered being an ADR was headache (11.0, 11.4 and 13.3 % with perampanel 4, 8 and 12 mg/day vs. 11.3 % with placebo).
Serious TEAEs were reported by 3.5, 5.6 and 8.2 % of perampanel 4, 8 and 12 mg/day recipients compared with 5.0 % of placebo recipients. Serious psychiatric disorder TEAEs were reported by 1.2 % of perampanel recipients versus 0.9 % of placebo recipients. Moreover, psychic and behavioural TEAEs generally occurred within the first 6 weeks of treatment with perampanel. The studies revealed that in perampanel 2-12 mg/day recipients, suicide related TEAEs occurred with a similar frequency to that in placebo recipients (2 patients each faced such an event).
Clinically significant weight gain (greater than 7 % increase in bodyweight) occurred in 14.0, 15.3 and 15.4 % of perampanel 4, 8 and 12 mg/day recipients compared with 7.1 % of placebo recipients.

The EU SmPC includes warnings or precautions about suicidal ideation (as this has been reported in patients treated with AEDs in various indications), aggression (cases have been reported with perampanel, more frequently at higher dosages) and abuse potential. US prescribing information includes a boxed warning for serious psychiatric and behaviour reactions.

1. Plosker, G. L. Perampanel As Adjunctive Therapy in Patients with Partial-Onset Seizures. CNS Drugs 2012, 26, 1085-1096. (FMO only)
2. Frampton, J. E. Perampanel: A Review in Drug-Resistant Epilepsy. Drugs. 2015, 75(14), 1657-1668. (FMO only)
3. Hibi, S.; et. al. Discovery of 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (perampanel): a novel, noncompetitive a-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonist. J Med Chem 2012, 55(23), 10584-10600. (FMO only)
4. Arimoto, I.; et. al. Method for producing 1, 2-dihydropyridine-2-one compound. US20070142640A1
5. Perampanel USFDA Approval (free copy)