JNJ-64619178 | 2086772-26-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: JNJ-64619178
• 英文别名: JNJ‑64619178；Onametostat；(1S,2R,3S,5R)-3-[2-(2-amino-3-bromoquinolin-7-yl)ethyl]-5-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol
• CAS: 2086772-26-9
• 化学式: C₂₂H₂₃BrN₆O₂
• 分子量: 483.368
• InChiKey: DBSMLQTUDJVICQ-CJODITQLSA-N

物化性质

• 沸点：
  636.2±50.0 °C(Predicted)
• 密度：
  1.79±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO:111.0(最大浓度 mg/mL);229.64(最大浓度 mM)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  136
• 氢给体数：
  4
• 氢受体数：
  7

安全信息

• 危险类别：
  9
• 危险性防范说明：
  P260,P264,P270,P273,P280,P301+P312+P330,P304+P312,P305+P351+P338,P314,P337+P313,P391,P501
• 危险品运输编号：
  3077
• 危险性描述：
  H302,H319,H332,H372,H400
• 包装等级：
  III
• 储存条件：
  -20℃

制备方法与用途

生物活性

OnAMetostat (JNJ-64619178) 是一种 PRMT5 抑制剂，具有较高的选择性和效力（PRMT5-MEP-50, IC50=0.14 nM），并且表现出良好的药代动力学特性和安全性。

靶点

Target	Value
PRMT5	0.14 nM

体外研究

JNJ-64619178 可结合 SAM 结合口袋，以时间依赖性方式抑制 PRMT/MEP50 的功能。不同细胞系对 JNJ-64619178 的敏感度各异，这表明 JNJ-64619178 对 PRMT5 抑制主要依赖于基因组因素，而非一般的靶向性细胞毒性。

体内研究

每天口服给予 10 mg/kg JNJ-64619178 可选择性和有效地阻止 SMD1/3 蛋白的甲基化。SMD1/3 是剪接体的关键组成成分及 PRMT5/MEP50 的底物。在生物标记驱动的人类小细胞肺癌移植瘤模型（NCI-H1048）中，JNJ-64619178 可以引起肿瘤消退，并且在终止给药后仍然可以延长肿瘤生长抑制作用。

反应信息

• 作为产物：
  描述：

  (3aS,4R,6S,6aR)-4-(4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyl-4,5,6,6a-tetrahydro-3aH-cyclopenta[d][1,3]dioxole-6-carbaldehyde 在 ammonium hydroxide 、 potassium carbonate 、 9-硼双环[3.3.1]壬烷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 为溶剂， 反应 20.0h， 生成 JNJ-64619178
  参考文献：
  名称：

  [EN] NOVEL 6-6 BICYCLIC AROMATIC RING SUBSTITUTED NUCLEOSIDE ANALOGUES FOR USE AS PRMT5 INHIBITORS
  [FR] NOUVEAUX ANALOGUES NUCLÉOSIDIQUES SUBSTITUÉS PAR UN CYCLE AROMATIQUE BICYCLIQUE 6-6 UTILES COMME INHIBITEURS DE PRMT5

  摘要：

  本发明涉及新颖的6-6双环芳香环取代核苷类似物，其化学式为（I），其中变量的含义如权利要求中所定义。根据本发明的化合物可用作PRMT5抑制剂。该发明还涉及包含所述化合物作为活性成分的药物组合物，以及将所述化合物用作药物的用途。

  公开号：

  WO2017032840A1

文献信息

• Use of biomarkers in identifying cancer patients that will be responsive to treatment with a PRMT5 inhibitor
  申请人：Janssen Pharmaceutica NV

  公开号：US11279970B2

  公开（公告）日：2022-03-22

  The present disclosure describes methods of identifying a patient that is likely to be responsive to treatment with a protein arginine N-methyltransferase 5 (PRMT5) inhibitor. The methods include evaluating a biological sample from the patient for the presence of a spliceosome mutation or alteration, wherein the presence of the alteration indicates a higher likelihood for the patient to be responsive to treatment with the PRMT5 inhibitor than in the absence of the mutation or alteration.

  本公开说明描述了识别可能对蛋白质精氨酸N-甲基转移酶5（PRMT5）抑制剂治疗响应的患者的方法。该方法包括评估来自患者的生物样本中的剪接体突变或改变的存在，其中存在该改变表明患者对PRMT5抑制剂治疗的响应可能性比没有突变或改变的情况更高。
• 6-6 bicyclic aromatic ring substituted nucleoside analogues for use as PRMT5 inhibitors
  申请人：Janssen Pharmaceutica NV

  公开号：US10653711B2

  公开（公告）日：2020-05-19

  Embodiments of the present invention relate to 6-6 bicyclic aromatic ring substituted nucleoside analogues, including, for example, the following compound: Embodiments of the present invention also relate to uses of the disclosed compounds for the inhibition of protein arginine methyltransferase 5 (PRMT5).

  本发明的实施方案涉及 6-6 双环芳香环取代的核苷类似物，例如包括以下化合物： 本发明的实施方案还涉及所公开化合物在抑制蛋白精氨酸甲基转移酶5（PRMT5）方面的用途。
• NOVEL 6-6 BICYCLIC AROMATIC RING SUBSTITUTED NUCLEOSIDE ANALOGUES FOR USE AS PRMT5 INHIBITORS
  申请人：Janssen Pharmaceutica NV

  公开号：EP3341368B1

  公开（公告）日：2021-10-06
• METHODS OF TREATING CANCER USING PRMT5 INHIBITORS
  申请人：Janssen Pharmaceutica NV

  公开号：US20200384006A1

  公开（公告）日：2020-12-10

  The present disclosure provides methods for treating a human patient diagnosed with a cancer, comprising administering a therapeutically effective amount of a PRMT5 (protein arginine methyltransferase 5) inhibitor, certain methods comprising (i) administering to the patient initial doses of at least about 0.1 mg per day of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 5 to about 21 days; and (ii) administering to the patient subsequent doses of at least about 0.1 mg per day of the PRMT5 inhibitor for one or more subsequent dosing periods of about 5 to about 21 days each. In these methods, a first subsequent dosing period is separated in time from the initial dosing period by at least about 5 days and the subsequent dosing periods are separated in time from each other by at least about 5 days.
• [EN] METHODS OF TREATING CANCER USING PRMT5 INHIBITORS<br/>[FR] MÉTHODES DE TRAITEMENT DU CANCER À L'AIDE D'INHIBITEURS DE PRMT5
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2020245365A1

  公开（公告）日：2020-12-10

  The present disclosure provides methods for treating a human patient diagnosed with a cancer, comprising administering a therapeutically effective amount of a PRMT5 (protein arginine methyltransferase 5) inhibitor, certain methods comprising (i) administering to the patient initial doses of at least about 0.1 mg per day of the PRMT5 inhibitor that is (1S,2R,3S,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentane-1,2-diol or a pharmaceutically acceptable addition salt or solvate thereof for an initial dosing period of about 5 to about 21 days; and (ii) administering to the patient subsequent doses of at least about 0.1 mg per day of the PRMT5 inhibitor for one or more subsequent dosing periods of about 5 to about 21 days each. In these methods, a first subsequent dosing period is separated in time from the initial dosing period by at least about 5 days and the subsequent dosing periods are separated in time from each other by at least about 5 days.