1-benzyl-3-(5-chloro-2-fluorophenyl)-1-(1-(pentan-2-yl)piperidin-4-yl)urea

• 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: 1-benzyl-3-(5-chloro-2-fluorophenyl)-1-(1-(pentan-2-yl)piperidin-4-yl)urea
• 英文别名: SJ000859973-1；1-Benzyl-3-(5-chloro-2-fluorophenyl)-1-(1-pentan-2-ylpiperidin-4-yl)urea；1-benzyl-3-(5-chloro-2-fluorophenyl)-1-(1-pentan-2-ylpiperidin-4-yl)urea
• 化学式: C₂₄H₃₁ClFN₃O
• 分子量: 431.981
• InChiKey: ARNXJBQVHBNUCB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  35.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4-哌啶酮 在 三乙酰氧基硼氢化钠 、 potassium carbonate 、 溶剂黄146 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 51.0h， 生成 1-benzyl-3-(5-chloro-2-fluorophenyl)-1-(1-(pentan-2-yl)piperidin-4-yl)urea
  参考文献：
  名称：

  Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

  摘要：

  We previously reported the discovery, validation, and structure-activity relationships of a series of piperidinyl ureas that potently inhibit the DCN1-UBE2M interaction. We demonstrated that compound 7 inhibits both the DCN1- UBE2M protein-protein interaction and DCN1-mediated cullin neddylation in biochemical assays and reduces levels of steady-state cullin neddylation in a squamous carcinoma cell line harboring DCN1 amplification. Although compound 7 exhibits good solubility and permeability, it is rapidly metabolized in microsomal models (CLint = 170 mL/min/kg). This work lays out the discovery of an orally bioavailable analogue, NAcM-OPT (67). Compound 67 retains the favorable biochemical and cellular activity of compound 7 but is significantly more stable both in vitro and in vivo. Compound 67 is orally bioavailable, well tolerated in mice, and currently used to study the effects of acute pharmacologic inhibition of the DCN1-UBE2M interaction on the NEDD8/CUL pathway.

  DOI：

  10.1021/acs.jmedchem.7b01282

文献信息

• [EN] METHODS AND COMPOSITIONS OF INHIBITING DCN1-UBC12 INTERACTION<br/>[FR] PROCÉDÉS ET COMPOSITIONS D'INHIBITION DE L'INTERACTION DCN1-UBC12
  申请人：ST JUDE CHILDREN'S RES HOSPITAL

  公开号：WO2017049295A1

  公开（公告）日：2017-03-23

  In one aspect, the invention relates to substituted l-phenyl-3-(piperidin-4-yl)urea analogs, derivatives thereof, and related compounds, which are useful as inhibitors of the DCN1-UBC12 interaction inhibitors of DCN1 -mediated cullin-RING ligase activity, methods of making same, pharmaceutical compositions comprising same, methods of treating disorders using the disclosed compounds and compositions, methods of treating disorders associated with a DCN1-UBC12 interaction dysfunction, methods of treating disorders associated with a DCN1-mediated cullin-RING ligase activity dysfunction, methods of male contraception comprising the disclosed compounds and compositions, and kits comprising the disclosed compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，本发明涉及替代的l-苯基-3-(哌啶-4-基)脲类似物，其衍生物和相关化合物，这些化合物可用作DCN1-UBC12相互作用抑制剂和DCN1介导的卡林-环形酶活性抑制剂，制备方法，包含这些化合物的药物组合物，使用所披露的化合物和组合物治疗疾病的方法，治疗与DCN1-UBC12相互作用功能障碍相关的疾病的方法，治疗与DCN1介导的卡林-环形酶活性功能障碍相关的疾病的方法，包含所披露的化合物和组合物的男性避孕方法，以及包含所披露的化合物和组合物的试剂盒。本摘要旨在作为在特定领域进行搜索的扫描工具，并不打算限制本发明。
• Methods and compositions of inhibiting DCN1-UBC12 interaction
  申请人：Memorial Sloan Kettering Cancer Center

  公开号：US11116757B2

  公开（公告）日：2021-09-14

  In one aspect, the invention relates to substituted 1-phenyl-3-(piperidin-4-yl)urea analogs, derivatives thereof, and related compounds, which are useful as inhibitors of the DCN1-UBC12 interaction inhibitors of DCN1-mediated cullin-RING ligase activity, methods of making same, pharmaceutical compositions comprising same, methods of treating disorders using the disclosed compounds and compositions, methods of treating disorders associated with a DCN1-UBC12 interaction dysfunction, methods of treating disorders associated with a DCN1-mediated cullin-RING ligase activity dysfunction, methods of male contraception comprising the disclosed compounds and compositions, and kits comprising the disclosed compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，本发明涉及取代的1-苯基-3-(哌啶-4-基)脲类似物、其衍生物和相关化合物，它们可用作DCN1-UBC12相互作用的抑制剂DCN1介导的cullin-RING连接酶活性的抑制剂、制造方法、包含它们的药物组合物、使用所公开的化合物和组合物治疗疾病的方法、治疗与DCN1-UBC12相互作用功能障碍相关的疾病的方法、治疗与DCN1介导的cullin-RING连接酶活性障碍相关的疾病的方法、包含所公开化合物和组合物的男性避孕方法，以及包含所公开化合物和组合物的试剂盒。本摘要旨在作为在特定技术领域进行搜索的扫描工具，并非对本发明的限制。
• METHODS AND COMPOSITIONS OF INHIBITING DCN1-UBC12 INTERACTION
  申请人：Memorial Sloan Kettering Cancer Center

  公开号：US20210069172A1

  公开（公告）日：2021-03-11

  In one aspect, the invention relates to substituted 1-phenyl-3-(piperidin-4-yl)urea analogs, derivatives thereof, and related compounds, which are useful as inhibitors of the DCN1-UBC12 interaction inhibitors of DCN1-mediated cullin-RING ligase activity, methods of making same, pharmaceutical compositions comprising same, methods of treating disorders using the disclosed compounds and compositions, methods of treating disorders associated with a DCN1-UBC12 interaction dysfunction, methods of treating disorders associated with a DCN1-mediated cullin-RING ligase activity dysfunction, methods of male contraception comprising the disclosed compounds and compositions, and kits comprising the disclosed compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
• Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation
  作者：Jared T. Hammill、Deepak Bhasin、Daniel C. Scott、Jaeki Min、Yizhe Chen、Yan Lu、Lei Yang、Ho Shin Kim、Michele C. Connelly、Courtney Hammill、Gloria Holbrook、Cynthia Jeffries、Bhuvanesh Singh、Brenda A. Schulman、R. Kiplin Guy

  DOI：10.1021/acs.jmedchem.7b01282

  日期：2018.4.12

  We previously reported the discovery, validation, and structure-activity relationships of a series of piperidinyl ureas that potently inhibit the DCN1-UBE2M interaction. We demonstrated that compound 7 inhibits both the DCN1- UBE2M protein-protein interaction and DCN1-mediated cullin neddylation in biochemical assays and reduces levels of steady-state cullin neddylation in a squamous carcinoma cell line harboring DCN1 amplification. Although compound 7 exhibits good solubility and permeability, it is rapidly metabolized in microsomal models (CLint = 170 mL/min/kg). This work lays out the discovery of an orally bioavailable analogue, NAcM-OPT (67). Compound 67 retains the favorable biochemical and cellular activity of compound 7 but is significantly more stable both in vitro and in vivo. Compound 67 is orally bioavailable, well tolerated in mice, and currently used to study the effects of acute pharmacologic inhibition of the DCN1-UBE2M interaction on the NEDD8/CUL pathway.