LDN-214117

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: LDN-214117
• 英文别名: 1-(4-(6-methyl-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl)phenyl)piperazine；Ldn-214117；1-[4-[6-methyl-5-(3,4,5-trimethoxyphenyl)pyridin-3-yl]phenyl]piperazine
• 化学式: C₂₅H₂₉N₃O₃
• 分子量: 419.524
• InChiKey: BHUXVRVMMYAXKN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 以30 mg的产率得到LDN-214117
  参考文献：
  名称：

  Structure–Activity Relationship of 3,5-Diaryl-2-aminopyridine ALK2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing Mutants

  摘要：

  There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in-diffuse intrinsic pontine ghoma (DIPG) tumors. Here we describe the structure-activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP AND TGF-beta type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-beta inhibiton. This study also highlights a potent 2-methylpyridine derivative 10 (LDN 214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG.

  DOI：

  10.1021/jm501177w

文献信息

• [EN] METHODS OF CULTURING AND/OR EXPANDING STEM CELLS AND/OR LINEAGE COMMITTED PROGENITOR CELLS USING AMIDO COMPOUNDS<br/>[FR] PROCÉDÉS DE CULTURE ET/OU D'EXPANSION DE CELLULES SOUCHES ET/OU DE CELLULES PROGÉNITRICES DÉTERMINÉES D'UNE LIGNÉE À L'AIDE DE COMPOSÉS AMIDO
  申请人：IDEAYA BIOSCIENCES INC

  公开号：WO2020018848A1

  公开（公告）日：2020-01-23

  Provided are methods for expanding stem cells and/or lineage committed progenitor cells, such as hematopoietic stems cells and/or lineage committed progenitor cells, at least in part, by using compounds that antagonize AhR. The compounds are represented by formulae (I) (II) (III) (IV), wherein the letters and symbols a, b, c, d, e, f, g, Z, R1b, R2a and R2b have the meanings provided in the specification. Also provided are compositions comprising stem cells and/or lineage committed progenitor cells expanded by methods disclosed herein and methods for the treatment of diseases treatable by same.

  提供了一种扩增干细胞和/或系谱承诺的前体细胞的方法，例如造血干细胞和/或系谱承诺的前体细胞，至少部分地通过使用拮抗AhR的化合物。这些化合物由公式 (I) (II) (III) (IV) 表示，其中字母和符号 a、b、c、d、e、f、g、Z、R1b、R2a 和 R2b 在说明书中有提供的含义。还提供了包含通过本文披露的方法扩增的干细胞和/或系谱承诺的前体细胞的组合物，以及用于治疗可通过相同方法治疗的疾病的方法。
• [EN] COMPOSITIONS AND METHODS FOR INHIBITING BMP<br/>[FR] COMPOSITIONS ET PROCÉDÉS D'INHIBITION DE LA BMP
  申请人：BRIGHAM & WOMENS HOSPITAL

  公开号：WO2015148654A1

  公开（公告）日：2015-10-01

  The present invention provides small molecule inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. These compounds and compositions may be used to modulate cell growth, di.fferentia.tion, proliferation, and apoptosis, and thus may be useful tor treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. These compounds and compositions may also be used to reduce circulating levels of ApoB- 100 or LDL and treat or prevent acquired or congenital, hypercholesterolemia or hyperlipoproteinemia; diseases, disorders, or syndromes associated with defects in lipid absorption or metabolism; or diseases, disorders, or syndromes caused by hyperlipidemia.

  本发明提供了BMP信号通路的小分子抑制剂，以及用于抑制BMP信号通路的组成物和方法。这些化合物和组成物可用于调节细胞生长、分化、增殖和凋亡，因此可用于治疗与BMP信号通路相关的疾病或病况，包括炎症、心血管疾病、血液疾病、癌症和骨骼疾病，以及用于调节细胞分化和/或增殖。这些化合物和组成物也可用于减少ApoB-100或LDL的循环水平，治疗或预防获得性或先天性高胆固醇血症或高脂蛋白血症；与脂质吸收或代谢缺陷相关的疾病、疾病或综合症；或由高脂血症引起的疾病、疾病或综合症。
• METHOD FOR PRODUCING CELL MASS INCLUDING PITUITARY TISSUE, AND CELL MASS THEREOF
  申请人：Sumitomo Chemical Company, Limited

  公开号：EP3715450A1

  公开（公告）日：2020-09-30

  The present invention aims to provide a method for efficiently producing a cell mass containing pituitary tissue from pluripotent stem cells. A method for producing a cell mass containing pituitary tissue, including the following steps (1) and (2): (1) a first step of suspension-culturing pluripotent stem cells to form a cell aggregate in the presence of a Wnt signal transduction pathway inhibiting substance, (2) a second step of suspension-culturing the aggregate obtained in the first step in the presence of a BMP signal transduction pathway activating substance and a Sonic hedgehog signal transduction pathway activating substance, thereby obtaining a cell mass comprising pituitary tissue.

  本发明旨在提供一种利用多能干细胞高效生产含有垂体组织的细胞团的方法。一种生产含有垂体组织的细胞团的方法，包括以下步骤（1）和（2）： (1) 第一步，在 Wnt 信号转导通路抑制物质的存在下，悬浮培养多能干细胞以形成细胞团、 (2) 第二步，在 BMP 信号转导通路激活物质和 Sonic hedgehog 信号转导通路激活物质存在的情况下，悬浮培养第一步中获得的聚集体，从而获得包含垂体组织的细胞团。
• RETINAL GANGLION CELL DEATH INHIBITOR
  申请人：Senju Pharmaceutical Co., Ltd.

  公开号：EP3875117A1

  公开（公告）日：2021-09-08

  The present invention relates to a retinal ganglion cell death suppressor comprising a BMPR signal transduction inhibitor, a drug comprising a BMPR signal transduction inhibitor for protecting retinal neurons, and a pharmaceutical composition using these for preventing or treating a disease involving retinal ganglion cell death, such as glaucoma, diabetic retinopathy and retinal vascular occlusion.

  本发明涉及一种包含 BMPR 信号转导抑制剂的视网膜神经节细胞死亡抑制剂，一种包含 BMPR 信号转导抑制剂的用于保护视网膜神经元的药物，以及一种使用这些药物的药物组合物，用于预防或治疗涉及视网膜神经节细胞死亡的疾病，如青光眼、糖尿病视网膜病变和视网膜血管闭塞。
• CELL AGGREGATION INCLUDING OLFACTORY NEURON OR PRECURSOR CELL THEREOF, AND METHOD FOR PRODUCING SAME
  申请人：SUMITOMO CHEMICAL COMPANY LIMITED

  公开号：EP3842527A1

  公开（公告）日：2021-06-30

  A method for producing a cell cluster including an olfactory receptor neuron or a precursor cell thereof, comprising the following steps (1) to (3): step (1) of suspension-culturing a pluripotent stem cell in the presence of a Wnt signaling pathway inhibitory substance to form a cell aggregate; step (2) of suspension-culturing the cell aggregate obtained in the step (1) in the presence of a BMP signaling pathway-activating substance; and step (3) of suspension-culturing the cell aggregate obtained in the step (2) to obtain the cell cluster, wherein step (3) comprises at least one step selected from the group consisting of: step (3a) of suspension-culturing in the presence of an FGF signaling pathway-activating substance; step (3b) of suspension-culturing in the presence of a BMP signaling pathway inhibitory substance; and step (3c) of culturing in the presence of an FGF signaling pathway-activating substance and a BMP signaling pathway inhibitory substance.

  一种生产包括嗅觉受体神经元或其前体细胞的细胞团的方法，包括以下步骤(1)至(3)：步骤(1)在Wnt信号通路抑制物质存在下悬浮培养多能干细胞以形成细胞聚集体；步骤(2)在BMP信号通路激活物质存在下悬浮培养步骤(1)中获得的细胞聚集体；以及步骤(3)悬浮培养步骤(2)中获得的细胞聚集体以获得细胞簇，其中步骤(3)包括至少一个选自由以下组成的组的步骤：在 FGF 信号通路激活物质存在下进行悬浮培养的步骤(3a)； 在 BMP 信号通路抑制物质存在下进行悬浮培养的步骤(3b)；以及 在 FGF 信号通路激活物质和 BMP 信号通路抑制物质存在下进行培养的步骤(3c)。