Synthesis and pharmacological evaluation of primary amino acid derivatives (PAADs): novel neurological agents for the treatment of epilepsy and neuropathic pain Public Deposited

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  • March 21, 2019
Creator
  • King, Amber M.
    • Affiliation: Eshelman School of Pharmacy, Division of Chemical Biology and Medicinal Chemistry
Abstract
  • Epilepsy and neuropathic pain (NP) are chronic neurological disorders that result from dysregulations in neuronal function. Currently, there is a lack of adequate therapeutic agents available to treat these disorders and the need remains to develop compounds that possess a novel mechanism of action to address the shortcomings of current medications. Recently, the role of voltage-gated sodium channels (VGSCs) has been implicated in the pathophysiological mechanisms of NP, while their role in epilepsy has been known for some time. The functionalized amino acid (FAA) (R)-lacosamide is an emerging antiepileptic drug (AED) that has been shown to selectively promote VGSCs into the slow inactivated state and has recently been approved by the EMEA and the US FDA under the trademark Vimpat[registered trademark] for the adjuvant treatment of partial-onset seizures in adults. (R)-Lacosamide has also demonstrated clinical efficacy in treating painful diabetic neuropathy, but has yet to gain regulatory approval for this indication. The pharmaceutical industry has made advances in developing peripheral nervous system (PNS)-specific agents that target specific isoforms of VGSCs for the treatment of NP. We combined the concept of PNS-selectivity with our knowledge of FAAs and proposed that primary amino acid derivatives (PAADs) may selectively target PNS receptor sites, thereby avoiding potential CNS side effects that makes adherence to pain therapy difficult. Additionally, we examined the effect of PAADs on CNS function due to the excellent anticonvulsant activity of FAAs. We synthesized and evaluated over 50 PAADs in whole animal models of epilepsy and NP, and developed a structure-activity relationship (SAR) that defined the structural requirements for PAAD activity. The SAR revealed excellent anticonvulsant activity and pain attenuation for a novel class of compounds, the C(2)-hydrocarbon PAADs. Then, we synthesized over 40 additional PAADs to optimize anticonvulsant activity and pain attenuation. From our optimization studies, we discovered two PAADs that displayed superior anticonvulsant activity and may rival the therapeutic capabilities of (R)-lacosamide. Finally, we evaluated the most active PAADs in a series of binding and enzymatic assays but we did not reveal any new binding targets of therapeutic relevance.
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmaceutical Sciences at the Eshelman School of Pharmacy (Division of Medicinal Chemistry and Natural Products)."
Advisor
  • Kohn, Harold
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Chapel Hill, NC
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  • Open access
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