Neurogate Therapeutics, Inc.

RALEIGH, NC, United States

Neurogate Therapeutics, Inc.

RALEIGH, NC, United States

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Torregrosa R.,Neurogate Therapeutics, Inc. | Yang X.-F.,University of Arizona | Dustrude E.T.,Paul and Carole Stark Neurosciences Research Institute | Wang Y.,University of Arizona | And 10 more authors.
Journal of Medicinal Chemistry | Year: 2014

We prepared 13 derivatives of N-(biphenyl-4′-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound's whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed. © 2014 American Chemical Society.


Torregrosa R.,Neurogate Therapeutics, Inc. | Yang X.-F.,University of Arizona | Dustrude E.T.,Indiana University | Cummins T.R.,Indiana University | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

Six novel 3″-substituted (R)-N-(phenoxybenzyl) 2-N-acetamido-3-methoxypropionamides were prepared and then assessed using whole-cell, patch-clamp electrophysiology for their anticonvulsant activities in animal seizure models and for their sodium channel activities. We found compounds with various substituents at the terminal aromatic ring that had excellent anticonvulsant activity. Of these compounds, (R)-N-4′-((3″-chloro)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-5) and (R)-N-4′-((3″-trifluoromethoxy)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-9) exhibited high protective indices (PI = TD50/ED50) comparable with many antiseizure drugs when tested in the maximal electroshock seizure test to mice (intraperitoneally) and rats (intraperitoneally, orally). Most compounds potently transitioned sodium channels to the slow-inactivated state when evaluated in rat embryonic cortical neurons. Treating HEK293 recombinant cells that expressed hNaV1.1, rNaV1.3, hNaV1.5, or hNaV1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation. © 2015 Elsevier Ltd. All rights reserved.


Park K.D.,University of North Carolina at Chapel Hill | Park K.D.,Korea Institute of Science and Technology | Yang X.-F.,University of Arizona | Dustrude E.T.,Paul and Carole Stark Neurosciences Research Institute | And 6 more authors.
ACS Chemical Neuroscience | Year: 2015

The functionalized amino acid, lacosamide ((R)-2), and the α-aminoamide, safinamide ((S)-3), are neurological agents that have been extensively investigated and have displayed potent anticonvulsant activities in seizure models. Both compounds have been reported to modulate voltage-gated sodium channel activity. We have prepared a series of chimeric compounds, (R)-7-(R)-10, by merging key structural units in these two clinical agents, and then compared their activities with (R)-2 and (S)-3. Compounds were assessed for their ability to alter sodium channel kinetics for inactivation, frequency (use)-dependence, and steady-state activation and fast inactivation. We report that chimeric compounds (R)-7-(R)-10 in catecholamine A-differentiated (CAD) cells and embryonic rat cortical neurons robustly enhanced sodium channel inactivation at concentrations far lower than those required for (R)-2 and (S)-3, and that (R)-9 and (R)-10, unlike (R)-2 and (S)-3, produce sodium channel frequency (use)-dependence at low micromolar concentrations. We further show that (R)-7-(R)-10 displayed excellent anticonvulsant activities and pain-attenuating properties in the animal formalin model. Of these compounds, only (R)-7 reversed mechanical hypersensitivity in the tibial-nerve injury model for neuropathic pain in rats. © 2014 American Chemical Society.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 248.93K | Year: 2012

DESCRIPTION (provided by applicant): Epilepsy is a set of disorders that result from neuronal hyperexcitability and hypersynchronous neuronal firing. Epilepsy remains a major widespread neurological concern. Current medications do not meet the health needsof 30% of epilepsy patients, and approximately 40% of patients experience serious side effects. So, the need for novel, more effective therapies is apparent. NeuroGate Therapeutics (NGT) has advanced a novel class of agents termed Extended NeuroAmides (ENAs), which have exhibited, in established animal seizure models, superb anticonvulsant activities comparable or better than most antiepileptic drugs. Recent studies have documented that the sodium channel slow inactivation (SI) state is a valid target forepilepsy. NGT has demonstrated that ENAs preferentially, potently, and stereospecifically transition Na+ channels into the SI state, and show frequency (use)-dependency. ENA Na+ channel SI activity far exceeded that of any reported anticonvulsant agent. These findings indicated that ENAs can reduce the pathological activity associated with neuronal hyperexcitability (sustained depolarization, high-frequency spiking) without significantly disrupting normal physiological activity. ENAs have shown no interactions with receptors known to adversely impact drug effectiveness. In this proposal, NGT requests funds to identify the optimal ENA that would permit investigational new drug (IND)-enabling studies in the STTR phase II grant. In Specific Aim 1, NGT will build upon an evolving structure-activity relationship study using synthesis, whole animal pharmacology that determines efficacy and neurotoxicity, and CAD cell patch-clamp electrophysiology to identify ENAs of interest. Four selected ENAs will be tested for CYP-450 inhibition and evaluated by electrophysiology using hippocampal cells. In Specific Aim 2, NGT will evaluate the two most promising ENAs in recombinant cell lines that express CNS Na+ channels (NaV1.1, NaV1.2, NaV1.3, NaV1.6) and cardiac NaV1.5 channel in order to gain information on mechanism of action and safety. In Specific Aim 3, NGT will evaluate the bioavailability in the rat of the most promising ENA and the utility of this ENA for treating pharmacoresistant epilepsy. Identifying an optimized ENA for the IND-enabling studies will permit NGT to advance a compound for clinical testing, with the support of phase II STTR funding. PUBLIC HEALTH RELEVANCE: Epilepsy is a serious neurological disorder that affects 1% of the world population andfor which current medications are ineffective for 30% of patients. We have identified a new class of compounds, termed Extended NeuroAmides, that exhibit potent activities in established anticonvulsant animal models and that function by a unique mechanismof action. The proposed investigation provides a critical path for ENA development and selection allowing for IND- enabling studies in the STTR phase II study.


PubMed | Indiana University, Indiana University School of Medicine - Terre Haute, Neurogate Therapeutics, Inc., University of Arizona and University of North Carolina at Chapel Hill
Type: Journal Article | Journal: Bioorganic & medicinal chemistry | Year: 2015

Six novel 3-substituted (R)-N-(phenoxybenzyl) 2-N-acetamido-3-methoxypropionamides were prepared and then assessed using whole-cell, patch-clamp electrophysiology for their anticonvulsant activities in animal seizure models and for their sodium channel activities. We found compounds with various substituents at the terminal aromatic ring that had excellent anticonvulsant activity. Of these compounds, (R)-N-4-((3-chloro)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-5) and (R)-N-4-((3-trifluoromethoxy)phenoxy)benzyl 2-N-acetamido-3-methoxypropionamide ((R)-9) exhibited high protective indices (PI=TD50/ED50) comparable with many antiseizure drugs when tested in the maximal electroshock seizure test to mice (intraperitoneally) and rats (intraperitoneally, orally). Most compounds potently transitioned sodium channels to the slow-inactivated state when evaluated in rat embryonic cortical neurons. Treating HEK293 recombinant cells that expressed hNaV1.1, rNaV1.3, hNaV1.5, or hNaV1.7 with (R)-9 recapitulated the high levels of sodium channel slow inactivation.

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