Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Nov 27;56(22):9019-30.
doi: 10.1021/jm400894u. Epub 2013 Nov 11.

Novel, broad-spectrum anticonvulsants containing a sulfamide group: pharmacological properties of (S)-N-[(6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112)

David F McComsey  1 , Virginia L Smith-Swintosky, Michael H Parker, Douglas E Brenneman, Ewa Malatynska, H Steve White, Brian D Klein, Karen S Wilcox, Michael E Milewski, Mark Herb, Michael F A Finley, Yi Liu, Mary Lou Lubin, Ning Qin, Allen B Reitz, Bruce E Maryanoff
Affiliations

Novel, broad-spectrum anticonvulsants containing a sulfamide group: pharmacological properties of (S)-N-[(6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112)

David F McComsey et al. J Med Chem. .

Abstract

Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such "neurostabilizers" have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4-9, 10a-i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels and was effective as a K(+) channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Frequency distribution analysis for individual rats (N = 8 animals) in the hippocampal kindling model after treatment with various anticonvulsants (4, 3, 1, ethosuximide, phenytoin, carbamazepine, and valproic acid; vehicle: 0.5% aqueous methylcellulose). The color code represents the number of rats out of eight that evinced the particular seizure response noted (seizure free, focal seizure, global seizure). Seizure scores were assessed at the time of peak effect and at the maximal effective dose.
Scheme 1
Scheme 1
Synthesis of 4.a a. Alcohols Ia and Ib were prepared as a mixture of regioisomers (~3:1) by following a reported enantioselective synthesis (ref 12). The ratio of IIIa:IIIb was ~3:1. Amine llla was purified as the HCl salt. Ts, p-toluenesulfonyl; phth, phthalimide anion.
Scheme 2
Scheme 2
Synthesis of 12.
Chart 1
Chart 1
Sulfamate and Sulfamide Anticonvulsants (with Standard Numbering System)
See this image and copyright information in PMC

References

    1. World Health Organization. [2 June 2013];Media Center, Epilepsy Fact Sheet. http://www.who.int/mediacentre/factsheets/fs999/en/index.html.
    1. White HS, Smith MD, Wilcox KS. Mechanisms of action of antiepileptic drugs. Int Rev Neurobiol. 2007;81:85–110. - PubMed
    2. Calabresi P, Galletti F, Rossi C, Sarchielli P, Cupini LM. Antiepileptic drugs in migraine: from clinical aspects to cellular mechanisms. Trends Pharmacol Sci. 2007;28:188–195. - PubMed
    3. Landmark CJ. Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs. 2008;22:27–47. - PubMed
    4. Ettinger AB, Argoff CE. Use of antiepileptic drugs for nonepileptic conditions: psychiatric disorders and chronic pain. Neurotherapeutics. 2007;4:75–83. - PMC - PubMed
    5. Zaremba PD, Bialek M, Blaszczyk B, Cioczek P, Czuczwar SJ. Non-epilepsy uses of antiepileptic drugs. Pharmacol Rep. 2006;58:1–12. - PubMed
    6. Maryanoff BE. Pharmaceutical “gold” from neurostabilizing agents: topiramate and successor molecules. J Med Chem. 2009;52:3431–3440. - PubMed
    1. Maryanoff BE, Nortey SO, Gardocki JF, Shank RP, Dodgson SP. Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate and related compounds. J Med Chem. 1987;30:880–887. - PubMed
    2. Shank RP, Gardocki JF, Vaught JL, Davis CB, Schupsky JJ, Raffa RB, Dodgson SJ, Nortey SO, Maryanoff BE. Topiramate: preclinical evaluation of a structurally novel anticonvulsant. Epilepsia. 1994;35:450–460. - PubMed
    3. Maryanoff BE, Margul BL. Topiramate. Drugs Future. 1989;14:342–344.
    4. Maryanoff BE. Sugar sulfamates for seizure control: discovery and development of topiramate, a structurally unique antiepileptic drug. Curr Top Med Chem. 2009;9:1048–1061. - PubMed

    1. TOPAMAX® (topiramate) attained peak, annual global sales of $2.7 billion in 2008, as indicated in the 2008 Johnson & Johnson Annual Report, p 23 (http://www.jnj.com/wps/wcm/connect/a9a1fd804d5592ab9b16db1bc89e29c7/2008_Annual_Report.pdf?MOD=AJPERES).

    1. Shank RP, Maryanoff BE. Molecular pharmacodynamics, clinical therapeutics, and pharmacokinetics of topiramate. CNS Neurosci Ther. 2008;14:120–142. - PMC - PubMed

MeSH terms

LinkOut - more resources