N-(2-((R)-1-(cis-4-hydroxy-4-(6-methylpyridin-3-yl)cyclohexyl)pyrrolidin-3-ylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(2-((R)-1-(cis-4-hydroxy-4-(6-methylpyridin-3-yl)cyclohexyl)pyrrolidin-3-ylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide
• 化学式: C₂₆H₃₁F₃N₄O₃
• 分子量: 504.552
• InChiKey: ANPZZLAVOITWAV-RQTOMXEWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.16
• 重原子数：
  36.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  94.56
• 氢给体数：
  3.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  间三氟甲基马尿酸 在 N-甲基吗啉 、 氢气 、 palladium(II) hydroxide 、 三乙酰氧基硼氢化钠 作用下， 以 四氢呋喃 、 甲醇 为溶剂， -15.0~20.0 ℃ 、379.22 kPa 条件下， 反应 1.58h， 生成 N-(2-((R)-1-(cis-4-hydroxy-4-(6-methylpyridin-3-yl)cyclohexyl)pyrrolidin-3-ylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide 、 N-(2-((R)-1-(trans-4-hydroxy-4-(6-methylpyridin-3-yl)cyclohexyl)pyrrolidin-3-ylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist

  摘要：

  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 mu M 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).

  DOI：

  10.1021/ml200030q

文献信息

• Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist
  作者：Chu-Biao Xue、Hao Feng、Ganfeng Cao、Taisheng Huang、Joseph Glenn、Rajan Anand、David Meloni、Ke Zhang、Lingquan Kong、Anlai Wang、Yingxin Zhang、Changsheng Zheng、Michael Xia、Lihua Chen、Hiroyuki Tanaka、Qi Han、D. J. Robinson、Dilip Modi、Lou Storace、Lixin Shao、Vaqar Sharief、Mei Li、Laurine G. Galya、Maryanne Covington、Peggy Scherle、Sharon Diamond、Tom Emm、Swamy Yeleswaram、Nancy Contel、Kris Vaddi、Robert Newton、Greg Hollis、Steven Friedman、Brian Metcalf

  DOI：10.1021/ml200030q

  日期：2011.6.9

  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 mu M 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).