CC趋化因子受体8（CCR8）强效小分子拮抗剂的设计、合成及优化进展
Design, synthesis, and progress toward optimization of potent small molecule antagonists of CC chemokine receptor 8 (CCR8).
作者信息
Ghosh Shomir, Elder Amy, Guo Jianping, Mani Ukti, Patane Michael, Carson Kenneth, Ye Qing, Bennett Robert, Chi Shannon, Jenkins Tracy, Guan Bing, Kolbeck Roland, Smith Sean, Zhang Cheng, LaRosa Gregory, Jaffee Bruce, Yang Hua, Eddy Priya, Lu Chuang, Uttamsingh Vinita, Horlick Robert, Harriman Geraldine, Flynn Daniel
机构信息
Department of Medicinal Chemistry, Millennium Pharmaceuticals, 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA.
出版信息
J Med Chem. 2006 May 4;49(9):2669-72. doi: 10.1021/jm050965z.
Activation of CCR8 by its ligand CCL1 may play an important role in diseases such as asthma, multiple sclerosis, and cancer. The study of small molecule CCR8 antagonists will help establish the validation of these hypotheses. We report the design, synthesis, and progress toward optimization of potent small molecule CCR8 antagonists identified from a high-throughput screen. These analogues exhibit good potency in binding and chemotaxis assays, show good selectivity versus the hERG channel, and have good eADME (early absorption, distribution, metabolism, and excretion) profiles.
其配体CCL1对CCR8的激活可能在哮喘、多发性硬化症和癌症等疾病中发挥重要作用。对小分子CCR8拮抗剂的研究将有助于验证这些假设。我们报告了从高通量筛选中鉴定出的强效小分子CCR8拮抗剂的设计、合成及优化进展。这些类似物在结合和趋化性测定中表现出良好的效力，对hERG通道具有良好的选择性，并且具有良好的早期吸收、分布、代谢和排泄（eADME）特性。
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