Lacosamide | Treatment of Partial-Onset Seizures | Slow Inactivator of Voltage Gated Sodium Channels (VGSCs) | Modulator of Collapsin-Response Mediator Protein-2 (CRMP-2)

Lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropionamide] also referred to as harkoseride is a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates. Later, experimental studies proved Lacosamide to be an efficacious anticonvulsant in animal models [1, 2].

Lacosamide demonstrated broad anticonvulsant effects in murine seizure models for generalized seizures, complex partial-onset seizures, and status epilepticus. In the maximal electroshock seizure (MES) test, Lacosamide was more potent than phenytoin or phenobarbital.

Lacosamide: 2D and 3D Structure

It causes a general decrease in neuronal discharge frequency and synaptic excitability in laboratory testing. Since these actions are not mediated at major excitatory (AMPA/NMDA) or inhibitory (GABA_A) postsynaptic receptors, the mechanism of action of Lacosamide was initially unknown [2].

Later, two different probable mechanisms of action were discovered. Lacosamide selectively enhances slow inactivation of sodium channels. Second, Lacosamide binds to the collapsin response mediator protein-2 (CRMP-2) and modulates mCRMP2 function in vitro [2].

Lacosamide tablets are indicated for use alone or as add-on therapy in the treatment of partial-onset (focal) seizures in patients with epilepsy who are 17 years of age or older (in EU it is 16 years and older).

In August 2008, Lacosamide was granted market authorization by the European Commission as an adjunctive therapy for partial-onset seizures with or without secondary generalization in patients with epilepsy. It was approved by the FDA as an adjunctive therapy for partial-onset seizures in October 2008.

Epilepsy and Antiepileptic Drugs (AEDs) 

Epilepsy is one of the most common neurological disorders, and is estimated to affect ~3% of the general population at some point in their lives1. There are three clinical types of partial seizures including simple partial, complex partial, and partial seizure evolving into secondarily generalized seizures.

In general, carbamazepine is considered firstline therapy for partial-onset seizures. However, less than 50% of patients will remain seizure-free after beginning initial antiepileptic drug (AED) therapy. If carbamazepine fails to control the seizures, lamotrigine, topiramate, tiagabine, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and zonisamide may be either added to carbamazepine or used as monotherapy. Although these agents have demonstrated similar efficacy for the treatment of partial-onset seizures, they are not always well tolerated by patients. In fact, 20-30% of patients will discontinue therapy because of intolerable adverse drug effects (ADEs). Based upon the percentage of patients with epilepsy who are refractory to or unable to tolerate AEDs due to ADEs, it is evident that effective AEDs with minimal adverse drug reactions are needed. Therefore, a need remains for AEDs with improved effectiveness and tolerability [1].

Lacosamide has Dual Mode of Action

Experimental results suggest that Lacosamide has a dual mode of action underlying its anticonvulsant and analgesic activity.  Lacosamide appears to selectively enhance sodium channel slow inactivation, with no effects on fast inactivation. Classical sodium channel modulators selectively enhance fast inactivation. Since slow inactivation of sodium channels is an endogenous mechanism by which neurons reduce ectopic hyperactivity, this modulation represents an effective mechanism to selectively reduce pathophysiological hyperactivity, while leaving physiological activity intact.

In contrast, some antiepileptic drugs (AEDs), such as carbamazepine, phenytoin, and lamotrigine, affect the fast inactivation of voltage-gated sodium channels. The enhancement of slow inactivation induced by Lacosamide may help normalize activation thresholds and decrease pathophysiological neuronal activity, thus controlling neuronal hyperexcitability [3, 4].

Furthermore, employing proteomic affinity-labeling techniques, collapsin-response mediator protein 2 (CRMP-2 alias DRP-2) was identified as a binding partner. Follow-up experiments confirmed a functional interaction of Lacosamide with CRMP-2 in vitro. It is unclear whether the effect on this protein is stimulatory or inhibitory, but as a consequence, Lacosamide appears to attenuate the effects of neurotrophic factors on axon outgrowth.

Dosages and Approvals:

Lacosamide (Tradename: Vimpat) should be initiated at 50 mg twice daily for the adjunctive treatment of partial-onset seizures. The dose can be increased weekly by 100 mg daily given as two divided doses, up to the recommended total daily dose of 200 or 400 mg. The Food and Drug Administration (FDA) did not approve the 600 mg total daily dose, due to no additional benefit and the increased risk of additional side effects over a 400 mg total daily dose.

Patients receiving IV Lacosamide can receive a dosage equivalent to their oral Lacosamide dose. The IV dose should be infused over 30-60 min. The injection may be injected without further dilution and is compatible with sodium chloride injection 0.9%, lactated ringers, and dextrose.

Lacosamide is available as 50 mg, 100 mg, 150 mg, and 200 mg tablets. It is also available in a 200 mg/20 mL single dose vial, which is stable at room temperature.

Lacosamide was discovered at the University of Houston and developed initially by Schwarz Bioscienes. Union Chimique Belge (UCB) later acquired Schwarz and developed Lacosamide for the adjunctive treatment of partial-onset seizures and also trying Lacosamide as a therapy for neuropathic pains.

Reported Activities for Lacosamide

Lacosamide (10-100 uM) did not significantly bind (greater than 50% inhibition of radioligand binding) to any of more than 100 receptors, channels, or enzymes tested, including molecular targets of other drugs with analgesic and antiepileptic activity. Lacosamide did not modulate the uptake of the neurotransmitters: norepinephrine, dopamine, or serotonin into synaptosomes, and did not bind to GABA transporters or influence the activity of GABA transaminases.

Lacosamide did bind weakly (25-50% inhibition of radioligand binding) to the sodium channel at batrachotoxin site 2. Lacosamide did not alter resting membrane potential or passive membrane properties following application of voltage ramps between -70 to +20 mV. No effect was observed on voltage-clamped Ca²⁺ channels (T-, L-, Nor P-type).

Moreover, its major desmethyl metabolite exerted no significant binding to the receptors tested [5].

Summary

Common name: SPM 927; SPM-927; SPM927; ADD 234034; ADD234034; ADD-234034; Harkoseride; LCM; Lacosamide

Trademarks: Vimpat

Molecular Formula: C13H18N2O3

CAS Registry Number: 175481-36-4

CAS Name: R-2-acetamido-N-benzyl-3-methoxypropionamide

Molecular Weight: 250.30

SMILES: O=C(N[C@@H](C(=O)NCc1ccccc1)COC)C

InChI Key: VPPJLAIAVCUEMN-GFCCVEGCSA-N

InChI: InChI=1S/C13H18N2O3/c1-10(16)15-12(9-18-2)13(17)14-8-11-6-4-3-5-7-11/h3-7,12H,8-9H2,1-2H3,(H,14,17)(H,15,16)/t12-/m1/s1

Mechanism of Action: Slow Inactivator of Voltage Gated Sodium Channels (VGSCs); Modulator of Collapsin-Response Mediator Protein-2 (CRMP-2)

Activity: Treatment of Partial-Onset Seizures in Adults with Epilepsy; Antiepileptic Drugs

Status: Launched 2008 (US, EU)             

Chemical Class: Amides; Amino Acids; Benzene; Small-molecules; D-serine

Originator: University of Houston/Union Chimique Belge

Lacosamide Synthesis

US20080027137A1: The synthetic route described in patent is reported on the largest scale and appears to be the most efficient with respect to overall yield, most amenable to scale up and avoids potential racemization of the chiral center. The synthesis starts with the methylation of NBoc-D-Serine with dimethylsulfate under phase transfer conditions (aqueous sodium hydroxide, toluene, tetrabutylammonium bromide) to give methyl ether in quantitative yield. Activation of the carboxylic acid of ether with isobutylchloroformate followed by reaction with benzylamine gave amide which was carried to the next step without isolation. Liberation of the amine was accomplished by reaction with HCl, and the resulting amine was treated with acetic anhydride to give Lacosamide in 70% yield and 99.8% ee.

J Med Chem 1996, 39(9), 1907-1916: The article discloses first reported synthetic steps for the preparation of Lacosamide and its derivatives. It also reports structure activity relationship and experimental data for all molecules. It reports a general synthesis for all and a modified one for Lacosamide and its analogues. The modified one is depicted in the diagram below:

Beginning with D-serine, treatment with acetic anhydride in acetic acid gave the N-acylated derivative, which was converted to N-benzylamide using the mixed anhydride coupling procedure. NMR and optical measurements indicated that both steps proceeded without racemization. Alkylation of N-benzylamide with MeI and Ag₂O gave (R)-N-benzyl-2-acetamido-3-methoxypropionamide in 30% overall yield.

Identifications:

1H NMR (Estimated) for Lacosamide

Experimental: ¹H NMR (CDCl₃) δ 2.04 (s), 3.38 (s), 3.43 (dd, J = 7.8, 9.0 Hz), 3.82 (dd, J = 4.2, 9.0 Hz) 4.48 (d, J = 6.0 Hz), 4.51-4.57 (m), 6.44 (br d, J = 5.4 Hz), 6.75 (br s), 7.25-7.37 (m).

13C-NMR (Estimated) for Lacosamide

Experimental: ¹³C NMR (CDCl₃) 23.2, 43.5, 52.4, 59.1, 71.7, 127.4, 127.5, 128.7, 137.9, 169.9, 170.3 ppm.

Addition of excess (R)-(-)-mandelic acid to a CDCl₃ solution of Lacosamide gave only one signal for the acetyl methyl and ether methyl protons.

Sideffects: Lacosamide was generally well tolerated in adult patients with partial-onset seizures. The adverse reactions (AEs) reported by at least 10% of patients were dizziness, ataxia, vomiting, diplopia (double vision), nausea, vertigo, and blurred vision. Less common side-effects include forgetfulness, discouragement, feelings of sadness, and lack of appetite.

In a study conducted to assess the teratogenic potential of AEDs in the zebrafish embryo, the teratogenicity index of Lacosamide was found to be higher than that of lamotigrine, levetiracetam, and ethosuximide. The FDA has assigned lacosamide to pregnancy category C.

Suicidal behavior and ideation have been observed as early as one week after starting treatment with Lacosamide, and is an adverse reaction from use of most AEDs.

Others: The apparent lack of sedative effects makes Lacosamide attractive for patients who are prone to develop somnolence with other AEDs. In addition, as Lacosamide can be effective against neuropathic pain attributed to distal diabetic neuropathy, patients with this co-morbidity might also benefit. On the other hand, reports of potential electrocardiogram changes with Lacosamide suggest that caution is needed before using this drug in patients with pre-existing cardiac disease and in those taking class I anti-arrhythmics or drugs known to cause PR prolongation [1].

References:

1. Perucca, E.; et. al. Lacosamide. Nature Reviews Drug Discovery 2008, 7, 973-974. (FMO only)

2. Harris, J.; et. al. Lacosamide and epilepsy. CNS Neurosci Ther 2011, 17(6), 678-682. (FMO only)

3. Halford, J. J.; et. al. Clinical perspectives on lacosamide. Epilepsy Curr 2009, 9(1), 1-9. (free article)

4. Beyreuther, B. K.; et. al. Lacosamide: a review of preclinical properties. CNS Drug Rev 2007, 13(1), 21-42. (FMO only)

5. Errington, A. C.; et. al. Seeking a mechanism of action for the novel anticonvulsant lacosamide. Neuropharmacology 2006, 50(8), 1016-1029. (FMO only)

6. Riedner, J.; et. al. Synthesis Scheme for Lacosamide. US20080027137A1

7. Choi, D.; et. al. Synthesis and anticonvulsant activities of N-Benzyl-2-acetamidopropionamide derivatives. J Med Chem 1996, 39(9), 1907-1916. (FMO only)

8. For more synthetic process from the literature feel free to send an email.

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