2. Academic Validation
  3. Pyrrolopyrimidine based CSF1R inhibitors: Attempted departure from Flatland

Pyrrolopyrimidine based CSF1R inhibitors: Attempted departure from Flatland

  • Eur J Med Chem. 2023 Dec 17:265:116053. doi: 10.1016/j.ejmech.2023.116053.
Frithjof Bjørnstad 1,  Simen Havik 2,  Thomas Ihle Aarhus 3,  Iktedar Mahdi 2,  Anke Unger 4,  Peter Habenberger 4,  Carsten Degenhart 4,  Jan Eickhoff 4,  Bert M Klebl 4,  Eirik Sundby 5,  Bård Helge Hoff 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491, Trondheim, Norway; Department of Material Science, Norwegian University of Science and Technology (NTNU), NO-7491, Trondheim, Norway.
  • 2 Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491, Trondheim, Norway.
  • 3 Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491, Trondheim, Norway; Lead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227, Dortmund, Germany.
  • 4 Lead Discovery Center GmbH (LDC), Otto-Hahn-Strasse 15, 44227, Dortmund, Germany.
  • 5 Department of Material Science, Norwegian University of Science and Technology (NTNU), NO-7491, Trondheim, Norway.
  • 6 Department of Chemistry, Norwegian University of Science and Technology (NTNU), Høgskoleringen 5, NO-7491, Trondheim, Norway. Electronic address: [email protected].
PMID: 38141285 DOI: 10.1016/j.ejmech.2023.116053
Abstract

The colony-stimulating factor 1 receptor (CSF1R) is an attractive target for inflammation disorders and cancers. Based on a series of pyrrolo[2,3-d]pyrimidine containing two carbo-aromatic rings, we have searched for new CSF1R inhibitors having a higher fraction of sp3-atoms. The phenyl unit in the 4-amino group could efficiently be replaced by tetrahydropyran (THP) retaining inhibitor potency. Exchanging the 6-aryl group with cyclohex-2-ene units also resulted in highly potent compounds, while fully saturated ring systems at C-6 led to a loss of activity. The structure-activity relationship study evaluating THP containing pyrrolo[2,3-d]pyrimidine derivates identified several highly active inhibitors by enzymatic studies. A comparison of 11 pairs of THP and aromatic compounds showed that inhibitors containing THP had clear benefits in terms of enzymatic potency, solubility, and cell toxicity. Guided by cellular experiments in Ba/F3 cells, five CSF1R inhibitors were further profiled in ADME assays, indicating the para-aniline derivative 16t as the most attractive compound for further development.

Keywords

CSF1R inhibitors; Kinase profiling; PLX3397; Pyrrolopyrimidine; Tetrahydropyran.

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