dc.contributor.author | Aarhus, Thomas Ihle | |
dc.contributor.author | Bjørnstad, Frithjof Andreas | |
dc.contributor.author | Wolowczyk, Camilla Izabel | |
dc.contributor.author | Larsen, Kristin Uhlving | |
dc.contributor.author | Rognstad, Line | |
dc.contributor.author | Leithaug, Trygve | |
dc.contributor.author | Unger, Anke | |
dc.contributor.author | Habenberger, Peter | |
dc.contributor.author | Wolf, Alexander | |
dc.contributor.author | Bjørkøy, Geir | |
dc.contributor.author | Pridans, Clare | |
dc.contributor.author | Eickhoff, Jan | |
dc.contributor.author | Klebl, Bert | |
dc.contributor.author | Hoff, Bård Helge | |
dc.contributor.author | Sundby, Eirik | |
dc.date.accessioned | 2023-12-14T08:18:39Z | |
dc.date.available | 2023-12-14T08:18:39Z | |
dc.date.created | 2023-06-12T09:36:14Z | |
dc.date.issued | 2023 | |
dc.identifier.citation | Journal of Medicinal Chemistry. 2023, 66 (10), 6959-6980. | en_US |
dc.identifier.issn | 0022-2623 | |
dc.identifier.uri | https://hdl.handle.net/11250/3107494 | |
dc.description.abstract | Colony-stimulating factor-1 receptor (CSF1R) is a receptor tyrosine kinase that controls the differentiation and maintenance of most tissue-resident macrophages, and the inhibition of CSF1R has been suggested as a possible therapy for a range of human disorders. Herein, we present the synthesis, development, and structure–activity relationship of a series of highly selective pyrrolo[2,3-d]pyrimidines, showing subnanomolar enzymatic inhibition of this receptor and with excellent selectivity toward other kinases in the platelet-derived growth factor receptor (PDGFR) family. The crystal structure of the protein and 23 revealed that the binding conformation of the protein is DFG-out-like. The most promising compounds in this series were profiled for cellular potency and subjected to pharmacokinetic profiling and in vivo stability, indicating that this compound class could be relevant in a potential disease setting. Additionally, these compounds inhibited primarily the autoinhibited form of the receptor, contrasting the behavior of pexidartinib, which could explain the exquisite selectivity of these structures. | en_US |
dc.language.iso | eng | en_US |
dc.publisher | ACS Publications | en_US |
dc.rights | Navngivelse 4.0 Internasjonal | * |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/deed.no | * |
dc.title | Synthesis and Development of Highly Selective Pyrrolo[2,3-d]pyrimidine CSF1R Inhibitors Targeting the Autoinhibited Form | en_US |
dc.title.alternative | Synthesis and Development of Highly Selective Pyrrolo[2,3-d]pyrimidine CSF1R Inhibitors Targeting the Autoinhibited Form | en_US |
dc.type | Peer reviewed | en_US |
dc.type | Journal article | en_US |
dc.description.version | publishedVersion | en_US |
dc.source.pagenumber | 6959-6980 | en_US |
dc.source.volume | 66 | en_US |
dc.source.journal | Journal of Medicinal Chemistry | en_US |
dc.source.issue | 10 | en_US |
dc.identifier.doi | 10.1021/acs.jmedchem.3c00428 | |
dc.identifier.cristin | 2153607 | |
dc.relation.project | Norges forskningsråd: 223255 | en_US |
cristin.ispublished | true | |
cristin.fulltext | original | |
cristin.qualitycode | 2 | |