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  1. Article: Fluorinated Isoindolinone-Based Glucosylceramide Synthase Inhibitors with Low Human Dose Projections.

    Loughran, H Marie / Schirripa, Kathy M / Roecker, Anthony J / Breslin, Michael J / Tong, Ling / Fillgrove, Kerry L / Kuo, Yuhsin / Bleasby, Kelly / Collier, Hannah / Altman, Michael D / Ford, Melissa C / Newman, Justin A / Drolet, Robert E / Cosden, Mali / Jinn, Sarah / Flick, Rosemarie B / Liu, Xiaomei / Minnick, Christina / Watt, Marla L /
    Lemaire, Wei / Burlein, Christine / Adam, Gregory C / Austin, Lauren A / Marcus, Jacob N / Smith, Sean M / Fraley, Mark E

    ACS medicinal chemistry letters

    2023  Volume 15, Issue 1, Page(s) 123–131

    Abstract: Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing ...

    Abstract Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing to disease progression. Herein, we report the late-stage optimization of an orally bioavailable and CNS penetrant isoindolinone class of GCS inhibitors. Starting from advanced lead
    Language English
    Publishing date 2023-12-21
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.3c00436
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Pyrazole Ureas as Low Dose, CNS Penetrant Glucosylceramide Synthase Inhibitors for the Treatment of Parkinson's Disease.

    Roecker, Anthony J / Schirripa, Kathy M / Loughran, H Marie / Tong, Ling / Liang, Tao / Fillgrove, Kerry L / Kuo, Yuhsin / Bleasby, Kelly / Collier, Hannah / Altman, Michael D / Ford, Melissa C / Drolet, Robert E / Cosden, Mali / Jinn, Sarah / Hatcher, Nathan G / Yao, Lihang / Kandebo, Monika / Vardigan, Joshua D / Flick, Rosemarie B /
    Liu, Xiaomei / Minnick, Christina / Price, Laura A / Watt, Marla L / Lemaire, Wei / Burlein, Christine / Adam, Gregory C / Austin, Lauren A / Marcus, Jacob N / Smith, Sean M / Fraley, Mark E

    ACS medicinal chemistry letters

    2023  Volume 14, Issue 2, Page(s) 146–155

    Abstract: Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme ... ...

    Abstract Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi's with
    Language English
    Publishing date 2023-01-12
    Publishing country United States
    Document type Journal Article
    ISSN 1948-5875
    ISSN 1948-5875
    DOI 10.1021/acsmedchemlett.2c00441
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Biomarker discovery in rat plasma for estrogen receptor-alpha action.

    Holt, Tom G / Flick, Rosemarie B / Rohde, Ellen / Griffin, Patrick / Rohrer, Susan P

    Electrophoresis

    2005  Volume 26, Issue 23, Page(s) 4486–4494

    Abstract: To support in vivo screening efforts for estrogen receptor (ER) subtype selective therapeutic agents, we initiated work to discover surrogate markers (biomarkers) in blood plasma that would change in response to ER subtype-specific action. We used a ... ...

    Abstract To support in vivo screening efforts for estrogen receptor (ER) subtype selective therapeutic agents, we initiated work to discover surrogate markers (biomarkers) in blood plasma that would change in response to ER subtype-specific action. We used a proteomic approach employing strong anion exchange chromatography (SAX), PAGE, and MS to identify potential plasma markers for selective ER-alpha action. The methodology was used to compare blood from vehicle-treated rats to blood from rats treated with either 17beta-estradiol (an ER-alpha/ER-beta agonist) or compound 1 (17alpha-ethynyl-[3,2-c]pyrazolo-19-nor-4-androstene-17beta-ol, an ER-alpha-selective agonist). Blood samples were first fractionated by SAX to separate fractions containing dominant common plasma proteins from fractions enriched for less-abundant plasma proteins. 1-D PAGE analysis of fractions depleted of dominant plasma proteins revealed treatment-specific changes in protein profiles. Protein bands that changed reproducibly in response to ER-alpha action were excised from the gel, separated by capillary LC, and identified by microspray ESI-MS. Using this method, the plasma levels of two proteins, transthyretin and apolipoprotein E, were shown to decrease in response to ER-alpha agonism. The method lacked the sensitivity to identify the known, 1000-fold less-abundant, estrogenic marker prolactin (PRL). However, using a commercial RIA and immunoblots, we showed that PRL levels increase significantly in response to treatment with the ER-alpha selective agonist, compound 1.
    MeSH term(s) Animals ; Apolipoproteins E/blood ; Biomarkers/blood ; Blood Proteins/analysis ; Chromatography, Ion Exchange ; Electrophoresis, Polyacrylamide Gel ; Estradiol/administration & dosage ; Estradiol/analogs & derivatives ; Estradiol/pharmacology ; Estrogen Receptor alpha/agonists ; Estrogen Receptor alpha/physiology ; Female ; Nandrolone/administration & dosage ; Nandrolone/analogs & derivatives ; Nandrolone/pharmacology ; Prealbumin/analysis ; Proteomics ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Mass, Electrospray Ionization
    Chemical Substances 17-ethynyl-(3,2-c)pyrazolo-19-nor-4-androstene-17-ol ; Apolipoproteins E ; Biomarkers ; Blood Proteins ; Estrogen Receptor alpha ; Prealbumin ; Estradiol (4TI98Z838E) ; Nandrolone (6PG9VR430D)
    Language English
    Publishing date 2005-12
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 619001-7
    ISSN 1522-2683 ; 0173-0835
    ISSN (online) 1522-2683
    ISSN 0173-0835
    DOI 10.1002/elps.200500405
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1868: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  4. Article ; Online: Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus.

    Uslaner, Jason M / Parmentier-Batteur, Sophie / Flick, Rosemarie B / Surles, Nathaniel O / Lam, June S H / McNaughton, Caitlyn H / Jacobson, Marlene A / Hutson, Pete H

    Neuropharmacology

    2009  Volume 57, Issue 5-6, Page(s) 531–538

    Abstract: In the search for strategies to treat schizophrenia, attention has focused on enhancing NMDA receptor function. In vitro experiments show that metabotropic glutamate 5 receptor (mGluR5) activation enhances NMDA receptor activity, and in vivo experiments ... ...

    Abstract In the search for strategies to treat schizophrenia, attention has focused on enhancing NMDA receptor function. In vitro experiments show that metabotropic glutamate 5 receptor (mGluR5) activation enhances NMDA receptor activity, and in vivo experiments indicate that mGluR5 positive allosteric modulators (PAMs) are effective in preclinical assays measuring antipsychotic potential and cognition. Here we characterized the dose-effect function of CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide), an mGluR5 PAM, on novel object recognition memory in unimpaired Wistar Hannover rats (0, 10 or 30 mg/kg CDPPB) and animals with an MK-801-induced deficit (0, 3, 10, or 30 mg/kg CDPPB). In each experiment compound was given 30 min prior to the first exposure in order to affect acquisition/consolidation of the memory. In both cases, an inverted-U-shaped dose-effect function was observed, with lower doses improving recognition but higher doses having no effect. We then examined the effects of CDPPB (0, 3, 10, or 30 mg/kg) on markers of synaptic plasticity in prefrontal cortex and hippocampus, focusing on the expression and phosphorylation status of proteins involved in NMDA related signaling, including the NMDA receptor subunits NR1 and NR2B, the AMPA receptor subunit GluR1, alphaCa((2+))/CaM dependent Ser-Thr kinases II (alphaCaMKII), and the transcription factor CREB. Expression and phosphorylation of many of these proteins, particularly in the prefrontal cortex, were also characterized by an inverted-U-shaped dose-effect function. Taken together, these findings show that mGluR5 activation enhances NMDA receptor function and markers of neuronal plasticity commensurate with improvements in recognition memory. However, the effects of CDPPB are heavily dependent on dose, with higher doses being ineffective in improving recognition memory and producing downstream effects consistent with heightened NMDA receptor activation. These findings may have important implications for the development of mGluR5 PAMs to treat schizophrenia.
    MeSH term(s) Animals ; Benzamides/administration & dosage ; Benzamides/pharmacology ; Brain/drug effects ; Brain/physiology ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Central Nervous System Agents/administration & dosage ; Central Nervous System Agents/pharmacology ; Cyclic AMP Response Element-Binding Protein/metabolism ; Dizocilpine Maleate ; Dose-Response Relationship, Drug ; Hippocampus/drug effects ; Hippocampus/physiology ; Male ; Memory Disorders/chemically induced ; Memory Disorders/drug therapy ; Neuronal Plasticity/drug effects ; Neuronal Plasticity/physiology ; Phosphorylation/drug effects ; Prefrontal Cortex/drug effects ; Prefrontal Cortex/physiology ; Pyrazoles/administration & dosage ; Pyrazoles/pharmacology ; Rats ; Rats, Wistar ; Receptors, AMPA/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Recognition (Psychology)/drug effects ; Recognition (Psychology)/physiology
    Chemical Substances 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide ; Benzamides ; Central Nervous System Agents ; Cyclic AMP Response Element-Binding Protein ; NR1 NMDA receptor ; NR2B NMDA receptor ; Pyrazoles ; Receptors, AMPA ; Receptors, N-Methyl-D-Aspartate ; glutamate receptor ionotropic, AMPA 1 ; Dizocilpine Maleate (6LR8C1B66Q) ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 (EC 2.7.11.17)
    Language English
    Publishing date 2009-10
    Publishing country England
    Document type Journal Article
    ZDB-ID 218272-5
    ISSN 1873-7064 ; 0028-3908
    ISSN (online) 1873-7064
    ISSN 0028-3908
    DOI 10.1016/j.neuropharm.2009.07.022
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ui I Zs.242: Show issues Location:
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