1-Isopropyl-5-methyl-1H-pyrazole-4-sulfonyl chloride | 1006495-98-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-Isopropyl-5-methyl-1H-pyrazole-4-sulfonyl chloride
• 英文别名: 5-methyl-1-propan-2-ylpyrazole-4-sulfonyl chloride
• CAS: 1006495-98-2
• 化学式: C₇H₁₁ClN₂O₂S
• 分子量: 222.696
• InChiKey: YFLLOAAKOQLXAO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  60.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (R)-1-(1-乙基-6-三氟甲基-1H-苯并咪唑-2-基)-乙胺 、 1-Isopropyl-5-methyl-1H-pyrazole-4-sulfonyl chloride 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 (R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)ethyl)-1-isopropyl-5-methyl-1H-pyrazole-4-sulfonamide
  参考文献：
  名称：

  Identification and Optimization of Benzimidazole Sulfonamides as Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists with in Vivo Activity

  摘要：

  We report here a novel series of benzimidazole sulfonamides that act as antagonists of the S1P(1) receptor, identified by exploiting an understanding of the pharmacophore of a high throughput screening (HTS)-derived series of compounds described previously. Lead compound 2 potently inhibits SIP-induced receptor internalization in a cell-based assay (EC50 = 0.05 mu M), but has poor physical properties and metabolic stability. Evolution of this compound through structure-activity relationship development and property optimization led to in vivo probes such as 4. However, this compound was unexpectedly found to be a potent CYP3A inducer in human hepatocytes, and thus further chemistry efforts were directed at addressing this liability. By employing a pregnane X receptor (PXR) reporter gene assay to prioritize compounds for further testing in human hepatocytes, we identified lipophilicity as a key molecular property influencing the likelihood of P450 induction. Ultimately, we have identified compounds such as 46 and 47, which demonstrate the desired S1P(1) antagonist activity while having greatly reduced risk of CYP3A induction in humans. These compounds have excellent oral bioavailability in preclinical species and exhibit pharmacodynamic effects of S1P(1) antagonism in several in vivo models following oral dosing. Relatively modest antitumor activity was observed in multiple xenograft models, however, suggesting that selective S1P(1) antagonists would have limited utility as anticancer therapeutics as single agents.

  DOI：

  10.1021/acs.jmedchem.5b01078