1,2-Dihydro-2-(4-chlorophenyl)-4-[3-(trifluoromethyl)phenyl]-6-methyldipyrazolo[3,4-b:3',4'-d]pyridine-3(6H)-one | 443146-92-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 1,2-Dihydro-2-(4-chlorophenyl)-4-[3-(trifluoromethyl)phenyl]-6-methyldipyrazolo[3,4-b:3',4'-d]pyridine-3(6H)-one
• 英文别名: 4-(4-chlorophenyl)-10-methyl-7-[3-(trifluoromethyl)phenyl]-3,4,8,10,11-pentazatricyclo[7.3.0.02,6]dodeca-1,6,8,11-tetraen-5-one
• CAS: 443146-92-7
• 化学式: C₂₁H₁₃ClF₃N₅O
• 分子量: 443.815
• InChiKey: RPACVNBASWYIPR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  31
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  63
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  三氟甲烷磺酸甲酯 、 1,2-Dihydro-2-(4-chlorophenyl)-4-[3-(trifluoromethyl)phenyl]-6-methyldipyrazolo[3,4-b:3',4'-d]pyridine-3(6H)-one 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.5h， 以82%的产率得到
  参考文献：
  名称：

  Structure–activity studies of a series of dipyrazolo[3,4- b :3′,4′- d ]pyridin-3-ones binding to the immune regulatory protein B7.1

  摘要：

  The interaction of co-stimulatory molecules on T cells with 137 molecules on antigen presenting cells plays an important role in the activation of naive T cells. Consequently, agents that disrupt these interactions should have applications in treatment of transplant rejection as well as autoimmune diseases. To this end, specific small molecule inhibitors of human B7.1 were identified and characterized. Herein, we report the identification of potent small molecule inhibitors of the B7.1-CD28 interaction. In a high-throughput screen we identified several leads that prevented the interaction of B7.1 with CD28 with activities in the nanomolar to low micromolar range. One of these, the dihydrodipyrazolopyridinone 1, was subsequently shown to bind the V-like domain of human B7.1 at equimolar stoichiometry. With this as a starting point, we report here the synthesis and initial in vitro structure-activity relationships of a series of these compounds. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00183-4
• 作为产物：
  描述：

  5-氨基-1-甲基吡唑-4-甲酸乙酯 在 sodium hydride 、 溶剂黄146 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 乙醇 为溶剂， 反应 32.0h， 生成 1,2-Dihydro-2-(4-chlorophenyl)-4-[3-(trifluoromethyl)phenyl]-6-methyldipyrazolo[3,4-b:3',4'-d]pyridine-3(6H)-one
  参考文献：
  名称：

  Structure–activity studies of a series of dipyrazolo[3,4- b :3′,4′- d ]pyridin-3-ones binding to the immune regulatory protein B7.1

  摘要：

  The interaction of co-stimulatory molecules on T cells with 137 molecules on antigen presenting cells plays an important role in the activation of naive T cells. Consequently, agents that disrupt these interactions should have applications in treatment of transplant rejection as well as autoimmune diseases. To this end, specific small molecule inhibitors of human B7.1 were identified and characterized. Herein, we report the identification of potent small molecule inhibitors of the B7.1-CD28 interaction. In a high-throughput screen we identified several leads that prevented the interaction of B7.1 with CD28 with activities in the nanomolar to low micromolar range. One of these, the dihydrodipyrazolopyridinone 1, was subsequently shown to bind the V-like domain of human B7.1 at equimolar stoichiometry. With this as a starting point, we report here the synthesis and initial in vitro structure-activity relationships of a series of these compounds. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00183-4

文献信息

• Dihydrodipyrazolopyridinone inhibitors of B7-1
  申请人：Wyeth

  公开号：US20040044024A1

  公开（公告）日：2004-03-04

  The present invention provides a compound of formula I and the use thereof for the immunotherapeutic treatment of transplant rejection, autoimmune disease or graft vs. host disease. 1

  本发明提供了一种I式化合物及其用于免疫治疗移植排斥、自身免疫疾病或移植物抗宿主病的用途。
• DASH INHIBITORS, AND USES RELATED THERETO
  申请人：Trustees of Tufts College

  公开号：US20190209525A1

  公开（公告）日：2019-07-11

  Disclosed are potent immuno-DASH inhibitors, and their use in the treatment of cell proliferative diseases.
• COMBINATION THERAPIES USING CASPASE-1 DEPENDENT ANTICANCER AGENTS AND PGE2 ANTAGONISTS
  申请人：Trustees of Tufts College

  公开号：US20200054655A1

  公开（公告）日：2020-02-20

  Disclosed are combination therapies including administration of Caspase-1 dependent anticancer agents and PGE2 antagonists, and the use of such therapies in the treatment of cell proliferative diseases.
• METHODS AND COMPOSITIONS FOR PROMOTING AND POTENTIATING T-CELL MEDIATED IMMUNE RESPONSES THROUGH ADCC TARGETING OF CD39 EXPRESSING CELLS
  申请人：Purinomia Biotech, Inc.

  公开号：US20210047425A1

  公开（公告）日：2021-02-18

  In combination with conventional therapies (e.g. targeted therapy, chemotherapy, and angiogenesis inhibitors, etc.), immunotherapies targeting checkpoint molecules have shown promise in the treatment of solid or liquid tumors. However, the role of non-tumor cells in the intratumoral microenvironment has indicated that ablation of these cells may be a key to mounting an effective immune response against the tumor which includes tumor infiltration of cytotoxic T-cells and other anti-tumor cells of the immune system. Rather than focusing on trying to inhibit the ectonucleotidase activity of CD39 as an enzyme that generates adenosine, the present invention instead utilizes CD39 expression to bring about intratumoral cell ablation by CD39-dependent ADCC.
• COMPOSITIONS AND METHODS FOR PREVENTING OR REVERSING T-CELL EXHAUSTION THROUGH ECTONUCLEOTIDASE INHIBITION AND ANTIBODY-MEDIATED TARGET CYTOSIS
  申请人：Beth Israel Deaconess Medical Center, Inc.

  公开号：US20210253731A1

  公开（公告）日：2021-08-19

  In combination with conventional therapies (e.g., targeted therapy, chemotherapy, and angiogenesis inhibitors etc.), immunotherapies targeting checkpoint molecules have shown promise in the treatment of solid or liquid tumors. However, apoptotic regulatory T cells (Treg) induced by such therapies often become more suppressive in the tumor microenvironment (TME), through increased generation of adenosine tightly controlled by ectonucleotidases, viz. CD39 and CD73. CD39/ENTPD1, a novel checkpoint molecule, is highly expressed and activated on the tumor vasculature and infiltrating immune cells, promoting tumor growth. Deletion or blockade of CD39 enhances anti-tumor activity by augmenting anti-tumor immune responses and inhibiting tumor angiogenesis. The present invention is based at least in part on the development of anti-CD39 antibodies which mediate CD39 downregulation on immune cells, such as T-cells with markers of T-cell exhaustion, and the demonstrated utility of these antibodies in blocking tumor growth with minimal side effects in pre-clinical models.