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  1. Article ; Online: Design and evaluation of pyrazolopyrimidines as KCNQ channel modulators.

    Osuma, Augustine T / Xu, Xiangdong / Wang, Zhi / Van Camp, Jennifer A / Freiberg, Gail M

    Bioorganic & medicinal chemistry letters

    2019  Volume 29, Issue 19, Page(s) 126603

    Abstract: Effective treatments of neuropathic pain have been a focus of many discovery programs. KCNQ (kv7) are voltage gated potassium channel openers that have the potential for the treatment of CNS disorders including neuropathic pain. Clinical studies have ... ...

    Abstract Effective treatments of neuropathic pain have been a focus of many discovery programs. KCNQ (kv7) are voltage gated potassium channel openers that have the potential for the treatment of CNS disorders including neuropathic pain. Clinical studies have suggested agents such as Retigabine to be a modulator of pain-like effects such as hyperalgesia and allodynia. In this paper, we describe the discovery and evaluation of a series of novel pyrazolopyrimidines and their affinity for potassium channels KCNQ2/3. These pyrazolopyrimidines have also shown good efficacy in the capsaicin-induced acute and secondary mechanical allodynia model and excellent pharmacokinetic properties, which may be superior to Retigabine.
    MeSH term(s) Drug Design ; Humans ; Hyperalgesia/drug therapy ; Ion Channel Gating/drug effects ; KCNQ Potassium Channels/antagonists & inhibitors ; Potassium Channel Blockers/chemistry ; Potassium Channel Blockers/pharmacology ; Pyrazoles/chemistry ; Pyrazoles/pharmacology ; Pyrimidines/chemistry ; Pyrimidines/pharmacology
    Chemical Substances KCNQ Potassium Channels ; Potassium Channel Blockers ; Pyrazoles ; Pyrimidines
    Language English
    Publishing date 2019-08-06
    Publishing country England
    Document type Evaluation Study ; Journal Article
    ZDB-ID 1063195-1
    ISSN 1464-3405 ; 0960-894X
    ISSN (online) 1464-3405
    ISSN 0960-894X
    DOI 10.1016/j.bmcl.2019.08.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3203: Show issues Location:
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  2. Article ; Online: The HPK1 Inhibitor A-745 Verifies the Potential of Modulating T Cell Kinase Signaling for Immunotherapy.

    Malchow, Sven / Korepanova, Alla / Panchal, Sanjay C / McClure, Ryan A / Longenecker, Kenton L / Qiu, Wei / Zhao, Hongyu / Cheng, Min / Guo, Jun / Klinge, Kelly L / Trusk, Patricia / Pratt, Steven D / Li, Tao / Kurnick, Matthew D / Duan, Lishu / Shoemaker, Alex R / Gopalakrishnan, Sujatha M / Warder, Scott E / Shotwell, J Brad /
    Lai, Albert / Sun, Chaohong / Osuma, Augustine T / Pappano, William N

    ACS chemical biology

    2022  Volume 17, Issue 3, Page(s) 556–566

    Abstract: Hematopoietic progenitor kinase 1 (HPK1) is an MAP4K family member within the Ste20-like serine/threonine branch of the kinome. HPK1 expression is limited to hematopoietic cells and has a predominant role as a negative regulator of T cell function. ... ...

    Abstract Hematopoietic progenitor kinase 1 (HPK1) is an MAP4K family member within the Ste20-like serine/threonine branch of the kinome. HPK1 expression is limited to hematopoietic cells and has a predominant role as a negative regulator of T cell function. Because of the central/dominant role in negatively regulating T cell function, HPK1 has long been in the center of interest as a potential pharmacological target for immune therapy. The development of a small molecule HPK1 inhibitor remains challenging because of the need for high specificity relative to other kinases, including additional MAP4K family members, that are required for efficient immune cell activation. Here, we report the identification of the selective and potent HPK1 chemical probe, A-745. In unbiased cellular kinase-binding assays, A-745 demonstrates an excellent cellular selectivity binding profile within pharmacologically relevant concentrations. This HPK1 selectivity translates to an
    MeSH term(s) Immunologic Factors ; Immunotherapy ; Protein Serine-Threonine Kinases ; Signal Transduction ; T-Lymphocytes
    Chemical Substances Immunologic Factors ; hematopoietic progenitor kinase 1 (EC 2.7.1.11) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
    Language English
    Publishing date 2022-02-21
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1554-8937
    ISSN (online) 1554-8937
    DOI 10.1021/acschembio.1c00819
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: A scalable approach to diaminopyrazoles using flow chemistry

    Wilson, Noel S / Osuma, Augustine T / Camp, Jennifer A.Van / Xu, Xiangdong

    Tetrahedron letters. 2012 Aug. 22, v. 53, no. 34

    2012  

    Abstract: This Letter reports on how the combination of microwave and continuous flow chemistry facilitated the convenient preparation of aminopyrazoles from commercial aryl halides. The method was applied to a variety of substrates with good to excellent yields ... ...

    Abstract This Letter reports on how the combination of microwave and continuous flow chemistry facilitated the convenient preparation of aminopyrazoles from commercial aryl halides. The method was applied to a variety of substrates with good to excellent yields and further extended toward the complete flow synthesis of 5,7-dimethyl-3-phenylpyrazolo[1,5-a]pyrimidin-2-amine.
    Keywords chemical reactions ; chemical structure ; halides ; organic compounds
    Language English
    Dates of publication 2012-0822
    Size p. 4498-4501.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 204287-3
    ISSN 1873-3581 ; 0040-4039
    ISSN (online) 1873-3581
    ISSN 0040-4039
    DOI 10.1016/j.tetlet.2012.05.152
    Database NAL-Catalogue (AGRICOLA)

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    Zs.A 2837: Show issues Location:
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