Discovery of selective Orai channel blockers bearing an indazole or a pyrazole scaffold.
| Autor: | Liardo E; Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA., Pham AT; Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA., Ghilardi AF; Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA., Zhelay T; Department of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine and College of Science and Mathematics, Wright State University, Dayton, OH, 45435, USA., Szteyn K; Department of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine and College of Science and Mathematics, Wright State University, Dayton, OH, 45435, USA., Gandi NL; Department of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine and College of Science and Mathematics, Wright State University, Dayton, OH, 45435, USA., Ekkati A; Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA., Koerner S; Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA., Kozak JA; Department of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine and College of Science and Mathematics, Wright State University, Dayton, OH, 45435, USA. Electronic address: juliusz.kozak@wright.edu., Sun L; Center for Drug Discovery and Translational Research, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. Electronic address: lsun1@bidmc.harvard.edu. |
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| Jazyk: | angličtina |
| Zdroj: | European journal of medicinal chemistry [Eur J Med Chem] 2024 Nov 15; Vol. 278, pp. 116805. Date of Electronic Publication: 2024 Aug 28. |
| DOI: | 10.1016/j.ejmech.2024.116805 |
| Abstrakt: | The calcium release activated calcium (CRAC) channel is highly expressed in T lymphocytes and plays a critical role in regulating T cell proliferation and functions including activation of the transcription factor nuclear factor of activated T cells (NFAT), cytokine production and cytotoxicity. The CRAC channel consists of the Orai pore subunit and STIM (stromal interacting molecule) endoplasmic reticulum calcium sensor. Loss of CRAC channel mediated calcium signaling has been identified as an underlying cause of severe combined immunodeficiency (SCID), leading to drastically weakened immunity against infections. Gain-of-function mutations in Orai and STIM have been associated with tubular aggregated myopathy (TAM), a skeletal muscle disease. While a number of small molecules have shown activity in inhibiting the CRAC signaling pathway, the usefulness of those tool compounds is limited by their off-target activity against TRPM4 and TRPM7 ion channels, high lipophilicity, and a lack of understanding of their mechanism of action. We report structure-activity relationship (SAR) studies that resulted in the characterization of compound 4k [1-(cyclopropylmethyl)-N-(3-fluoropyridin-4-yl)-1H-indazole-3-carboxamie] as a fast onset, reversible, and selective CRAC channel blocker. 4k fully blocked the CRAC current (IC Competing Interests: Declaration of competing interest All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024 Elsevier Masson SAS. All rights reserved.) |
| Databáze: | MEDLINE |
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