(R,E)-N-(1-(3-(2,2-difluoroethoxy)phenyl)ethyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pent-3-ene-1-sulfonamide | 1380335-80-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (R,E)-N-(1-(3-(2,2-difluoroethoxy)phenyl)ethyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pent-3-ene-1-sulfonamide
• 英文别名: (E)-N-[(1R)-1-[3-(2,2-difluoroethoxy)phenyl]ethyl]-5-(2,4-dioxopyrimidin-1-yl)pent-3-ene-1-sulfonamide
• CAS: 1380335-80-7
• 化学式: C₁₉H₂₃F₂N₃O₅S
• 分子量: 443.472
• InChiKey: MCNLOUKNJDKJSH-BAABZTOOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  30
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (R)-3-(N-(1-(3-(2,2-difluoroethoxy)phenyl)ethyl)-N-(methoxymethyl)sulfamoyl)propyl acetate 在 sodium hydride 、 二异丁基氢化铝 、 戴斯-马丁氧化剂 、 三苯基膦 、 甲胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 mineral oil 为溶剂， 反应 14.0h， 生成 (R,E)-N-(1-(3-(2,2-difluoroethoxy)phenyl)ethyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pent-3-ene-1-sulfonamide
  参考文献：
  名称：

  Discovery of Highly Potent Human Deoxyuridine Triphosphatase Inhibitors Based on the Conformation Restriction Strategy

  摘要：

  Human deoxyuridine triphosphatase (dUTPase) inhibition is a promising approach to enhance the efficacy of thymidylate synthase (TS) inhibitor based chemotherapy. In this study, we describe the discovery of a novel class of human dUTPase inhibitors based on the conformation restriction strategy. On the basis of the X-ray cocrystal structure of dUTPase and its inhibitor compound 7, we designed and synthesized two conformation restricted analogues, i.e., compounds 8 and 9. These compounds exhibited increased in vitro potency compared with the parent compound 7. Further structure activity relationship (SAR) studies identified a compound 43 with the highest in vitro potency (IC50 = 39 nM, EC50 = 66 nM). Furthermore, compound 43 had a favorable oral PK profile and exhibited potent antitumor activity in combination with 5-fluorouracil (5-FU) in the MX-1 breast cancer xenograft model. These results suggested that a dUTPase inhibitor may have potential for clinical usage.

  DOI：

  10.1021/jm300416h

文献信息

• Discovery of Highly Potent Human Deoxyuridine Triphosphatase Inhibitors Based on the Conformation Restriction Strategy
  作者：Seiji Miyahara、Hitoshi Miyakoshi、Tatsushi Yokogawa、Khoon Tee Chong、Junko Taguchi、Toshiharu Muto、Kanji Endoh、Wakako Yano、Takeshi Wakasa、Hiroyuki Ueno、Yayoi Takao、Akio, Fujioka、Akihiro Hashimoto、Kenjirou Itou、Keisuke Yamamura、Makoto Nomura、Hideko Nagasawa、Satoshi Shuto、Masayoshi Fukuoka

  DOI：10.1021/jm300416h

  日期：2012.6.14

  Human deoxyuridine triphosphatase (dUTPase) inhibition is a promising approach to enhance the efficacy of thymidylate synthase (TS) inhibitor based chemotherapy. In this study, we describe the discovery of a novel class of human dUTPase inhibitors based on the conformation restriction strategy. On the basis of the X-ray cocrystal structure of dUTPase and its inhibitor compound 7, we designed and synthesized two conformation restricted analogues, i.e., compounds 8 and 9. These compounds exhibited increased in vitro potency compared with the parent compound 7. Further structure activity relationship (SAR) studies identified a compound 43 with the highest in vitro potency (IC50 = 39 nM, EC50 = 66 nM). Furthermore, compound 43 had a favorable oral PK profile and exhibited potent antitumor activity in combination with 5-fluorouracil (5-FU) in the MX-1 breast cancer xenograft model. These results suggested that a dUTPase inhibitor may have potential for clinical usage.