2. Academic Validation
  3. Identification of Selective Imidazopyridine CSF1R Inhibitors

Identification of Selective Imidazopyridine CSF1R Inhibitors

  • ACS Med Chem Lett. 2024 Apr 30;15(5):722-730. doi: 10.1021/acsmedchemlett.4c00110.
John L Kane Jr 1,  Gary Asmussen 1,  Joseph Batchelor 1,  Mandy Cromwell 2,  Malika Fezoui 2,  Maria Fitzgerald 3,  Barret Giese 1,  Tatiana Gladysheva 1,  Stephanie Holley 1,  Kelly Keefe 2,  Michael Kothe 1,  Becky Lam 1,  Sungtaek Lim 1,  Jinyu Liu 1,  Liang Ma 1,  Markus Metz 1,  Andrew A Scholte 1,  Patrick Shum 1,  LinLi Wei 1,  Lisa Woodworth 2,  Andrea Edling 2
Affiliations

Affiliations

  • 1 Integrated Drug Discovery, Sanofi R&D, 350 Water Street, Cambridge, Massachusetts 02141, United States.
  • 2 Rare and Neurologic Disease Research, Sanofi R&D, 350 Water Street, Cambridge, Massachusetts 02141, United States.
  • 3 Drug Metabolism and Pharmacokinetics, Sanofi R&D, 350 Water Street, Cambridge, Massachusetts 02141, United States.
PMID: 38746878 DOI: 10.1021/acsmedchemlett.4c00110
Abstract

Colony stimulating factor-1 receptor (CSF1R or c-Fms), a class III receptor tyrosine kinase expressed on members of the mononuclear phagocyte system (MPS), plays a key role in the proper functioning of macrophages, microglia, and related cells. Aberrant signaling through CSF1R has been associated with a variety of disease states, including Cancer, inflammation, and neurodegeneration. In this Letter, we detail our efforts to develop novel CSF1R inhibitors. Drawing on previously described compounds, including GW2580 (4), we have discovered a novel series of compounds based on the imidazo[4,5-b]pyridine scaffold. Initial structure-activity relationship studies culminated in the identification of 36, a lead compound with potent CSF1R biochemical and cellular activity, acceptable in vitro ADME properties, and oral exposure in rat.

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