Optimization of a Potent Class of Arylamide Colony-Stimulating Factor-1 Receptor Inhibitors Leading to Anti-inflammatory Clinical Candidate 4-Cyano-N-[2-(1-cyclohexen-1-yl)-4-[1-[(dimethylamino

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• 作者：Carl R. Illig ; Carl L. Manthey ; Mark J. Wall ; Sanath K. Meegalla ; Jinsheng Chen ; Kenneth J. Wilson ; Shelley K. Ballentine ; Renee L. DesJarlais ; Carsten Schubert ; Carl S. Crysler ; Yanmin Chen ; Christopher J. Molloy ; Margery A. Chaikin ; Robert R. Donatelli ; Edward Yurkow ; Zhao Zhou ; Mark R. Player ; Bruce E. Tomczuk
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：November 24, 2011
• 年：2011
• 卷：54
• 期：22
• 页码：7860-7883
• 全文大小：819K
• 年卷期：v.54,no.22(November 24, 2011)
• ISSN：1520-4804

文摘

A class of potent inhibitors of colony-stimulating factor-1 receptor (CSF-1R or FMS), as exemplified by 8 and 21, was optimized to improve pharmacokinetic and pharmacodynamic properties and potential toxicological liabilities. Early stage absorption, distribution, metabolism, and excretion assays were employed to ensure the incorporation of druglike properties resulting in the selection of several compounds with good activity in a pharmacodynamic screening assay in mice. Further investigation, utilizing the type II collagen-induced arthritis model in mice, culminated in the selection of anti-inflammatory development candidate JNJ-28312141 (23, FMS IC₅₀ = 0.69 nM, cell assay IC₅₀ = 2.6 nM). Compound 23 also demonstrated efficacy in rat adjuvant and streptococcal cell wall-induced models of arthritis and has entered phase I clinical trials.