title: Structure-activity relationship study and discovery of indazole 3-carboxamides as calcium-release activated calcium channel blockers.
abstract: Aberrant activation of mast cells contributes to the development of numerous diseases including cancer, autoimmune disorders, as well as diabetes and its complications. The influx of extracellular calcium via the highly calcium selective calcium-release activated calcium (CRAC) channel controls mast cell functions. Intracellular calcium homeostasis in mast cells can be maintained via the modulation of the CRAC channel, representing a critical point for therapeutic interventions. We describe the structure-activity relationship study (SAR) of indazole-3-carboxamides as potent CRAC channel blockers and their ability to stabilize mast cells. Our SAR results show that the unique regiochemistry of the amide linker is critical for the inhibition of calcium influx, the release of the pro-inflammatory mediators β-hexosaminidase and tumor necrosis factor α by activated mast cells. Thus, the indazole-3-carboxamide 12d actively inhibits calcium influx and stabilizes mast cells with sub-μM IC50. In contrast, its reverse amide isomer 9c is inactive in the calcium influx assay even at 100μM concentration. This requirement of the specific 3-carboxamide regiochemistry in indazoles is unprecedented in known CRAC channel blockers. The new structural scaffolds described in this report expand the structural diversity of the CRAC channel blockers and may lead to the discovery of novel immune modulators for the treatment of human diseases.
authors.affiliation: Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Bai
authors.affiliation: Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Masazumi
authors.initials: M
authors.lastname: Nagai
authors.affiliation: Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Steffi K
authors.initials: SK
authors.lastname: Koerner
authors.affiliation: The Rongxiang Xu, MD Center for Regenerative Therapeutics, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Veves
authors.affiliation: Center for Drug Discovery and Translational Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: lsun1@bidmc.harvard.edu.
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000737:chemistry; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha
chemical_list: D000577:Amides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007191:Indazoles; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium
keywords: Calcium channel blockers; Indazole-3-carboxamides; Inflammation; Mast cell