John L. Kane Jr.*, Gary Asmussen, Joseph Batchelor, Mandy Cromwell, Malika Fezoui, Maria Fitzgerald, Barret Giese, Tatiana Gladysheva, Stephanie Holley, Kelly Keefe, Michael Kothe, Becky Lam, Sungtaek Lim, Jinyu Liu, Liang Ma, Markus Metz, Andrew A. Scholte, Patrick Shum, LinLi Wei, Lisa Woodworth and Andrea Edling,
{"title":"Identification of Selective Imidazopyridine CSF1R Inhibitors","authors":"John L. Kane Jr.*, Gary Asmussen, Joseph Batchelor, Mandy Cromwell, Malika Fezoui, Maria Fitzgerald, Barret Giese, Tatiana Gladysheva, Stephanie Holley, Kelly Keefe, Michael Kothe, Becky Lam, Sungtaek Lim, Jinyu Liu, Liang Ma, Markus Metz, Andrew A. Scholte, Patrick Shum, LinLi Wei, Lisa Woodworth and Andrea Edling, ","doi":"10.1021/acsmedchemlett.4c00110","DOIUrl":null,"url":null,"abstract":"<p >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 (<b>4</b>), we have discovered a novel series of compounds based on the imidazo[4,5-<i>b</i>]pyridine scaffold. Initial structure–activity relationship studies culminated in the identification of <b>36</b>, a lead compound with potent CSF1R biochemical and cellular activity, acceptable <i>in vitro</i> ADME properties, and oral exposure in rat.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00110","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.