强效、选择性且口服生物可利用的人CCR2拮抗剂INCB3284的发现。
Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist.
作者信息
Xue Chu-Biao, Feng Hao, Cao Ganfeng, Huang Taisheng, Glenn Joseph, Anand Rajan, Meloni David, Zhang Ke, Kong Lingquan, Wang Anlai, Zhang Yingxin, Zheng Changsheng, Xia Michael, Chen Lihua, Tanaka Hiroyuki, Han Qi, Robinson D J, Modi Dilip, Storace Lou, Shao Lixin, Sharief Vaqar, Li Mei, Galya Laurine G, Covington Maryanne, Scherle Peggy, Diamond Sharon, Emm Tom, Yeleswaram Swamy, Contel Nancy, Vaddi Kris, Newton Robert, Hollis Greg, Friedman Steven, Metcalf Brian
机构信息
Incyte Corporation , Experimental Station E336, Wilmington, Delaware 19880, United States.
出版信息
ACS Med Chem Lett. 2011 Mar 31;2(6):450-4. doi: 10.1021/ml200030q. eCollection 2011 Jun 9.
Abstract
We report the identification of 13 (INCB3284) as a potent human CCR2 (hCCR2) antagonist. INCB3284 exhibited an IC50 of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2, an IC50 of 4.7 nM in antagonism of chemotaxis activity, an IC50 of 84 μM in inhibition of the hERG potassium current, a free fraction of 58% in protein binding, high selectivity over other chemokine receptors and G-protein-coupled receptors, and acceptable oral bioavailability in rodents and primates. In human clinical trials, INCB3284 exhibited a pharmacokinetic profile suitable for once-a-day dosing (T 1/2 = 15 h).
摘要
我们报告了13（INCB3284）作为一种有效的人CCR2（hCCR2）拮抗剂的鉴定结果。INCB3284在拮抗单核细胞趋化蛋白-1与hCCR2结合方面的IC50为3.7 nM，在拮抗趋化活性方面的IC50为4.7 nM，在抑制hERG钾电流方面的IC50为84 μM，蛋白结合的游离分数为58%，对其他趋化因子受体和G蛋白偶联受体具有高选择性，并且在啮齿动物和灵长类动物中具有可接受的口服生物利用度。在人体临床试验中，INCB3284表现出适合每日一次给药的药代动力学特征（T 1/2 = 15小时）。
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