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Wellejus A.,Nensius Research A S | Elbrond-Bek H.,Nensius Research A S | Kelly N.M.,Nensius Research A S | Weidner M.S.,Nensius Research A S | Jorgensen S.H.,Nensius Research A S
Restorative Neurology and Neuroscience | Year: 2012

Purpose: Naturally occurring isothiocyanates (ITCs) are known to possess chemopreventive and neuroprotective properties. Our objective was to study the synthetic ITC 4-iodophenyl isothiocyanate (4-IPITC) in different models of neurodegeneration. Methods: In vitro, we exposed primary cortical neurons to various insults such as excessive glutamate exposure, oxygen-glucose deprivation, oxidative stress and 1-methyl-phenylpyridinium (MPP+). In vivo, experimental autoimmune encephalomyelitis (EAE) was induced in dark agouti rats treated with 4-IPITC in 3 different concentrations (10, 20 and 40 mg/kg), orally for 28 days. In a Parkinson's model, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) was injected in mice pretreated with 4-IPITC (5 mg/kg, orally) for 1 week. Nest building behavior at day 1, 3 and 6 after MPTP injection was assessed along with dopamine and metabolites, and tyrosine hydroxylase (TH) staining on termination day 6. Results: 4-IPITC successfully reduced cell death in all in vitro assays. Moreover, in two independent neurite outgrowth assays the compound showed neurotrophic properties. In the EAE study, 4-IPITC significantly delayed the day of onset and decreased the cumulative EAE score. Although the number of animals in this MPTP study was limited, 4-IPITC showed potential for dampening toxicity. Conclusions: Taken together, our in vitro findings suggest robust neuroprotective and neurotrophic properties of 4-IPITC, which was confirmed in two in vivo models of neurodegeneration. © 2012 - IOS Press and the authors. All rights reserved.


Elbrond-Bek H.,Nensius Research A S | Wellejus A.,Nensius Research A S | Kelly N.M.,Nensius Research A S | Weidner M.S.,Nensius Research A S | Jorgensen S.H.,Nensius Research A S
Neurochemistry International | Year: 2011

Focusing on development of novel drug candidates for the treatment of neurodegenerative diseases, we developed and synthesized a new compound, 2-(cyclohexylamino)-1-(4-cyclopentylpiperazin-1-yl)-2-methylpropan-1-one (amido-piperizine 1). The compound demonstrated robust neuroprotective properties after both glutamate excitotoxicity and peroxide induced oxidative stress in primary cortical cultures. Furthermore, amido-piperizine 1 was found to significantly induce neurite outgrowth in vitro which could suggest central reparative and regenerative potential of the compound. With these potential beneficial effects in CNS, the ability of the amido-piperizine 1 to penetrate the blood-brain barrier was tested using MDR1-MDCK cells. Amido-piperizine 1 was found not to be a P-gp substrate and to have a high blood-brain barrier penetration potential, indicating excellent availability to the CNS. Moreover, amido-piperizine 1 had a fast metabolic clearance rate in vitro, suggesting that parenteral in vivo administration seems preferable. As an attempt to elucidate a possible mechanism of action, we found that amido-piperizine 1 bound in nano-molar range to the sigma-1 receptor, which could explain the observed neuroprotective and neurotrophic properties, and with a 100-fold lower affinity to the sigma-2 receptor. These results propose that amido-piperizine 1 may hold promise as a drug candidate for the treatment of stroke/traumatic brain injury or other neurodegenerative diseases. © 2011 Elsevier B.V. All rights reserved.


Kelly N.M.,Nensius Research A S | Wellejus A.,Nensius Research A S | Elbrond-Bek H.,Nensius Research A S | Weidner M.S.,Nensius Research A S | Jorgensen S.H.,Nensius Research A S
Bioorganic and Medicinal Chemistry | Year: 2013

Esaprazole, a molecule previously acknowledged to protect against stomach and intestinal ulcers was surprisingly discovered to have neuroprotective activities and σ1 binding in vitro. A highly diverse set of Esaprazole analogues 2-5 was prepared in order to increase blood-brain barrier penetration. The analogues showed a structure-activity relationship at the σ1 receptor closely matching already published pharmacophores. Many of the analogues were shown to have neuroprotective properties in two assays using primary cultures of cortical neurons exposed to glutamate and hydrogen peroxide. However, no apparent SAR for these two assays could be developed. Metabolic stability of the analogues were also investigated and the structure of R1 had a significant bearing on the ADME properties of the compound resulting in two series of compounds. Compounds in which R 1 was a H or acyl group had good metabolic stability in RLM but poor BBB penetration, whereas compounds where R1 was a cyclo- or bicyclo-alkyl group had poor metabolic stability but good BBB penetration. © 2013 Elsevier Ltd. All rights reserved.


Kelly N.M.,Nensius Research A S | Wellejus A.,Nensius Research A S | Elbrond-Bek H.,Nensius Research A S | Weidner M.S.,Nensius Research A S | Jorgensen S.H.,Nensius Research A S
Synthetic Communications | Year: 2013

The reaction of the α-bromoamide 2a with 1-cyclopentylpiperazine gives the Favorskii-like rearranged product 4 when the reaction is heated to 70 °C in a mixture of aqueous potassium hydroxide and ethanol. However, when solid sodium carbonate/potassium iodide is used in ethanol, the nonrearranged product 3a is formed instead. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications® to view the free supplemental file. © 2013 Taylor and Francis Group, LLC.

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