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Vaughan D.,NeurAxon Inc. | Speed J.,NeurAxon Inc. | Medve R.,NeurAxon Inc. | Andrews J.S.,NeurAxon Inc.
Clinical therapeutics | Year: 2010

BACKGROUND: NXN-188 is a dual-action oral therapeutic being developed for the treatment of acute migraine. The mechanism of action of NXN-188 involves inhibition of both the neuronal nitric oxide synthase enzyme isoform and affinity for serotonin (5-hydroxytryptamine1B/D) receptors. OBJECTIVES: The aims of the initial Phase I clinical studies were to compare the pharmacokinetic (PK) properties of NXN-188 administered as a single dose or multiple twice-daily doses to healthy adult volunteers and to determine the tolerability of NXN-188 in these individuals. METHODS: Healthy adult male and female subjects were enrolled in 5 Phase I, randomized, double-blind studies, all of which (except for a fed/fasted trial) were placebo controlled. In the 4 single-dose studies, which differed with respect to feeding status and the formulation used (capsules or solution), subjects received NXN-188 at doses of 2 to 800 mg (0.027-11.2 mg/kg). In the repeat-dose study, subjects received 50-mg (0.71 mg/kg) doses twice daily for 4 days. Serum samples were analyzed for NXN-188 using validated HPLC-MS/MS methods. Standard clinical laboratory analyses (chemistry, hematology, and urinalysis) and measurements of serum creatine kinase and myoglobin levels were conducted at screening, admission, discharge, and follow-up. Baseline and postexposure values were compared to assess tolerability. Electrocardiography and physical examination were conducted at screening and at discharge and follow-up if any negative change occurred from the previous findings. Vital signs (heart rate, blood pressure, respiration), including assessment for orthostatic changes, were measured at screening, check-in, and follow-up visits (1 hour before dosing, every 30 minutes for the first 4 hours, then every hour for the next 4 hours, then every 4 hours for the remainder of the 24-hour study). Adverse events were recorded, reviewed, and monitored throughout the study. RESULTS: Two hundred three subjects (102 women, 101 men) 18 to 50 years of age were enrolled in the 5 studies; 168 subjects received NXN-188 and 35 received placebo. Most (91%) of the subjects were white; weight ranged from 69.3 to 71.8 kg (body mass index, 24.5-25.8 kg/m(2)). The initial absorption phase of orally administered NXN-188 peaked at approximately 1 hour, followed by a second absorption phase with a T(max) of approximately 4 to 5 hours. Exposure (C(max) and AUC) increased in a slightly greater than dose-proportional manner across a dose range of 2 to 800 mg (0.027-11.2 mg/kg). Elimination was multiexponential, with an initial rapid plasma drug elimination (plasma concentrations decreased approximately 70%-90% from Cmax within 24 hours after dosing), followed by a prolonged clearance phase of very low NXN-188 concentrations ( approximately 1%-5% of Cmax) that persisted for several weeks. Clearance ranged from 70 to 130 L/h, and the NXN-188 halflife ranged from 11 to 178 hours. Neither food nor gender had any measurable effect on the PK properties of NXN-188. Overall, dizziness was reported more often in the NXN-188 groups than in the placebo groups (6.3% vs 2.9%, respectively). Frequently reported adverse events that occurred more often in the placebo groups than in the NXN-188 groups were somnolence (11.4% vs 6.3%, respectively), and headache (8.6% vs 6.9%). Incidences of orthostatic hypotension (6.3% vs 5.7%) and postural (orthostatic) tachycardia syndrome (6.3% vs 5.7%) were comparable in the NXN-188 and placebo groups, respectively. No serious adverse events were reported at any dose of NXN-188 up to the current maximum dose (800 mg or 11.2 mg/kg). CONCLUSION: NXN-188 exhibited linear pharmaco-kinetics over the dose range studied and appeared to be well tolerated in these healthy volunteers.


Webster L.R.,Lifetree Clinical Research | Bath B.,Lifetree Clinical Research | Medve R.A.,Nektar Therapeutics | Medve R.A.,NeurAxon Inc. | And 2 more authors.
Pain Medicine (United States) | Year: 2012

Objective. The objective of this study was to evaluate the pharmacokinetics and abuse potential of different formulations of oxycodone. Design. The participants completed an 8-day, placebo-controlled trial with four phases: naloxone challenge, double-blind drug discrimination, double-blind abuse liability, and discontinuation. Subjects. Nineteen healthy, male, recreational drug abusers participated in this study. Interventions. The participants were administered different doses and formulations of oxycodone (40mg immediate release [IR], 40mg controlled release [CR], crushed 40mg CR, and 80mg CR) to evaluate pharmacokinetic parameters and ratings of drug liking and high. Outcome Measures. Pharmacokinetic parameters were determined over a 12-hour dosing interval. The primary pharmacodynamic endpoints were two questions from the Drug Effects Questionnaire ("Do you like the drug?" and "How high are you now?"). Results. Maximal plasma concentrations and area under the curve determinations were similar for 40mg IR, crushed 40mg CR, and 80mg CR, which were all greater than 40mg CR. For drug liking and high, the maximal effect and area under the effect curve were similar for the three formulations, which were all greater than 40mg CR. The dose required to produce comparable reports of drug liking and high was approximately twofold greater for the CR vs IR formulation. When the 40mg CR tablet was crushed, the pharmacokinetic and pharmacodynamic profile was similar to the 40mg IR formulation. Adverse events were consistent with opioid administration. Conclusions. Intact, orally administered oxycodone CR produced less drug liking and high than IR oxycodone, and required approximately twofold greater doses to produce subjective effects comparable to IR oxycodone. © Wiley Periodicals, Inc.


Renton P.,NeurAxon Inc. | Green B.,NeurAxon Inc. | Green B.,University of Toronto | Maddaford S.,NeurAxon Inc. | And 2 more authors.
ACS Medicinal Chemistry Letters | Year: 2012

A novel series of benzimidazole designed multiple ligands (DMLs) with activity at the neuronal nitric oxide synthase (nNOS) enzyme and the μ-opioid receptor was developed. Targeting of the structurally dissimilar heme-containing enzyme and the μ-opioid GPCR was predicated on the modulatory role of nitric oxide on μ-opioid receptor function. Structure-activity relationship studies yielded lead compound 24 with excellent nNOS inhibitory activity (IC 50 = 0.44 μM), selectivity over both endothelial nitric oxide synthase (10-fold) and inducible nitric oxide synthase (125-fold), and potent μ-opioid binding affinity, K i = 5.4 nM. The functional activity as measured in the cyclic adenosine monosphospate secondary messenger assay resulted in full agonist activity (EC 50 = 0.34 μM). This work represents a novel approach in the development of new analgesics for the treatment of pain. © 2012 American Chemical Society.


Hanessian S.,University of Montréal | Stoffman E.,University of Montréal | Mi X.,University of Montréal | Renton P.,NeurAxon Inc.
Organic Letters | Year: 2011

The scope of MacMillan's organocatalytic asymmetric conjugate addition reaction of indoles and electron-rich aromatics to α,β-unsaturated aldehydes has been extended to the use of 3-amino crotonaldehydes as substrates. The aromatics used include indoles as well as an aniline and a furan. The scope and effect of the groups on nitrogen (R, R′) has also been studied. The method has been applied to the concise synthesis of an advanced precursor to S-(+)-1, a drug prototype for the treatment of migraine headaches.(Figure Presented) © 2011 American Chemical Society.


Renton P.,NeurAxon Inc. | Speed J.,NeurAxon Inc. | Maddaford S.,NeurAxon Inc. | Annedi S.C.,NeurAxon Inc. | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

A series of 1,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase. A variety of flexible and restricted basic amine side chain substitutions was explored at the 1-position of the indole ring, while keeping the amidine group fixed at the 5-position. Compounds having N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)- (12, (R)-12, (S)-12 and 13) and N-(1-(1-methylazepan-4-yl)- side chains (14, 15, (-)-15 and (+)-15) showed increased inhibitory activity for the human nNOS isoform and selectivity over eNOS and iNOS isoforms. The most potent compound of the series for human nNOS (IC 50 = 0.02 μM) (S)-12 showed very good selectivity over the eNOS (eNOS/nNOS = 96-fold) and iNOS (iNOS/nNOS = 850-fold) isoforms. © 2011 Elsevier Ltd. All rights reserved.


Annedi S.C.,NeurAxon Inc. | Maddaford S.P.,NeurAxon Inc. | Mladenova G.,NeurAxon Inc. | Ramnauth J.,NeurAxon Inc. | And 7 more authors.
Journal of Medicinal Chemistry | Year: 2011

3,6-Disubstituted indole derivatives were designed, synthesized, and evaluated as inhibitors of human nitric oxide synthase (NOS). Bulky amine containing substitution on the 3-position of the indole ring such as an azabicyclic system showed better selectivity over 5- and 6-membered cyclic amine substitutions. Compound (-)-19 showed the best selectivity for neuronal NOS over endothelial NOS (90-fold) and inducible NOS (309-fold) among the current series. Compounds 16 and (-)-19 were shown to be either inactive or very weak inhibitors of human cytochrome P450 enzymes, indicating a low potential for drug-drug interactions. Compound 16 was shown to reverse thermal hyperalgesia in vivo in the Chung model of neuropathic pain. Compound 16 was also devoid of any significant vasoconstrictive effect in human coronary arteries, associated with the inhibition of human eNOS. These results suggest that 16 may be a useful tool for evaluating the potential role of selective nNOS inhibitors in the treatment of pain such as migraine and CTTH. © 2011 American Chemical Society.


The present invention features benzoxazines, benzothiazines, and related compounds that inhibit nitric oxide synthase (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isoforms. The NOS inhibitors of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing various medical conditions.


Patent
NeurAxon Inc. | Date: 2011-05-06

The present invention features inhibitors of nitric oxide synthase (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isoforms. The NOS inhibitors of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing conditions such as, for example, stroke, reperfusion injury, neurodegeneration, head trauma, CABG, migraine headache with and without aura, migraine with allodynia, central post-stroke pain (CPSP), neuropathic pain, morphine/opioid induced tolerance and hyperalgesia.


The present invention features benzoxazines, benzothiazines, and related compounds that inhibit nitric oxide synthase (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isoforms. The NOS inhibitors of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing various medical conditions.


Patent
NeurAxon Inc. | Date: 2013-10-21

The present invention features inhibitors of nitric oxide synthase (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isoforms. The NOS inhibitors of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing conditions such as, for example, stroke, reperfusion injury, neurodegeneration, head trauma, CABG, migraine headache with and without aura, migraine with allodynia, central post-stroke pain (CPSP), neuropathic pain, morphine/opioid induced tolerance and hyperalgesia.

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