pacritinib

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: pacritinib
• 英文别名: SB1518；11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triazatetracyclo[19.3.1.1^2,6.1^8,12]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene；11-(2-Pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(24),2(27),3,5,8(26),9,11,16,21(25),22-decaene；11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.12,6.18,12]heptacosa-1(24),2(27),3,5,8(26),9,11,16,21(25),22-decaene
• 化学式: C₂₈H₃₂N₄O₃
• 分子量: 472.587
• InChiKey: HWXVIOGONBBTBY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  68.7
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  pacritinib 、 Mal-PEG4-VaI-Cit-PAB-Cl 、 三氟乙酸 在 四丁基碘化铵 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 以57.3%的产率得到Mal-PEG4-Val-Cit-PAB-pacritinib
  参考文献：
  名称：

  [EN] INTERNALIZING BINDING MOLECULES
  [FR] INTERNALISATION DE MOLÉCULES DE LIAISON

  摘要：

  本发明涉及结合分子领域，其包括至少一个单一可变抗体结构域，针对纤维化效应细胞上存在的受体，例如肝纤维化中的活化肝星状细胞，肺纤维化中的活化间质成纤维细胞或血管平滑肌细胞，肾脏纤维化中的活化系膜或间质成纤维细胞，系统性硬化/硬皮病中的活化真皮成纤维细胞，炎症性肠病中的活化成纤维细胞，或者硬化恶性肿瘤中支持肿瘤的基质成纤维细胞。更具体地，本发明涉及内化结合分子，用于细胞特异性靶向输送抗纤维化物质。本发明还涉及一种结合分子，包括至少两个单一可变抗体结构域，每个结构域靶向上述纤维化效应细胞上的一个受体。本发明还涉及编码这种结合分子的核酸，表达这种结合分子的宿主细胞以及制备这种结合分子的方法。本发明还涉及包括这种结合分子的制药组合物以及这种结合分子和/或组合物的用途，特别是用于预防、治疗或诊断目的。

  公开号：

  WO2022060223A1
• 作为产物：
  描述：

  3-羟甲基苯硼酸 在 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 盐酸 、 四丁基硫酸氢铵 、 palladium diacetate 、 sodium carbonate 、 三苯基膦 、 potassium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基乙酰胺 、 水 、 正丁醇 为溶剂， 反应 27.5h， 生成 pacritinib
  参考文献：
  名称：

  Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma

  摘要：

  Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (ME). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for ME and lymphoma.

  DOI：

  10.1021/jm200326p

文献信息

• [EN] INTERNALIZING BINDING MOLECULES TARGETING RECEPTORS INVOLVED IN CELL PROLIFERATION OR CELL DIFFERENTIATION<br/>[FR] INTERNALISATION DE MOLÉCULES DE LIAISON CIBLANT DES RÉCEPTEURS IMPLIQUÉS DANS LA PROLIFÉRATION CELLULAIRE OU LA DIFFÉRENCIATION CELLULAIRE
  申请人：LINXIS B V

  公开号：WO2020185069A1

  公开（公告）日：2020-09-17

  The invention relates to the field of binding moleculescomprising at least one single variable antibody domain, targeted at receptors present on myofibroblasts and/or hepatic stellate cells (HSCs). The invention also relates to a binding molecule comprising at least two single variable antibody domains, each targeting a receptor on HSCs and/or on myofibroblasts. The invention further relates to nucleic acids encoding such binding molecules,a host cell for expression of such binding molecules and to methods for preparing such binding molecules. The invention further relates to pharmaceutical compositions that comprise such binding molecule and to uses of such binding molecules and/or compositions, in particular for prophylactic, therapeutic or diagnostic purposes.

  该发明涉及结合分子领域，其中至少包含一个单一可变抗体结构域，针对存在于肌成纤维细胞和/或肝星状细胞（HSCs）上的受体。该发明还涉及一种包含至少两个单一可变抗体结构域的结合分子，每个结构域针对HSCs和/或肌成纤维细胞上的一个受体。该发明还涉及编码这种结合分子的核酸，用于表达这种结合分子的宿主细胞以及制备这种结合分子的方法。该发明还涉及包含这种结合分子的药物组合物，以及这种结合分子和/或组合物的用途，特别是用于预防、治疗或诊断目的。
• Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), a Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma
  作者：Anthony D. William、Angeline C.-H. Lee、Stéphanie Blanchard、Anders Poulsen、Ee Ling Teo、Harish Nagaraj、Evelyn Tan、Dizhong Chen、Meredith Williams、Eric T. Sun、Kee Chuan Goh、Wai Chung Ong、Siok Kun Goh、Stefan Hart、Ramesh Jayaraman、Mohammed Khalid Pasha、Kantharaj Ethirajulu、Jeanette M. Wood、Brian W. Dymock

  DOI：10.1021/jm200326p

  日期：2011.7.14

  Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2(V617F)), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (ME). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2(WT) and JAK2(V617F), respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for ME and lymphoma.
• [EN] INTERNALIZING BINDING MOLECULES<br/>[FR] INTERNALISATION DE MOLÉCULES DE LIAISON
  申请人：LINXIS B V

  公开号：WO2022060223A1

  公开（公告）日：2022-03-24

  The invention relates to the field of binding molecules comprising at least one single variable antibody domain, targeted at receptors present on fibrogenic effector cells, such as activated hepatic stellate cells in liver fibrosis, activated interstitial fibroblasts or vascular smooth muscle cells in lung fibrosis, activated mesangial- or interstitial fibroblasts in renal fibrosis, activated dermal fibroblasts in systemic sclerosis/scleroderma, activated fibroblasts in inflammatory bowel disease, or tumor-supporting stromal fibroblasts in sclerosing malignant tumors. More in particular, the invention relates to internalizing binding molecules for cell-specific targeted delivery of anti-fibrotic substances. The invention also relates to a binding molecule comprising at least two single variable antibody domains, each targeting a receptor on said fibrogenic effector cells. The invention further relates to nucleic acids encoding such binding molecules, a host cell for expression of such binding molecules and to methods for preparing such binding molecules. The invention further relates to pharmaceutical compositions that comprise such binding molecule and to uses of such binding molecules and/or compositions, in particular for prophylactic, therapeutic or diagnostic purposes.

  本发明涉及结合分子领域，其包括至少一个单一可变抗体结构域，针对纤维化效应细胞上存在的受体，例如肝纤维化中的活化肝星状细胞，肺纤维化中的活化间质成纤维细胞或血管平滑肌细胞，肾脏纤维化中的活化系膜或间质成纤维细胞，系统性硬化/硬皮病中的活化真皮成纤维细胞，炎症性肠病中的活化成纤维细胞，或者硬化恶性肿瘤中支持肿瘤的基质成纤维细胞。更具体地，本发明涉及内化结合分子，用于细胞特异性靶向输送抗纤维化物质。本发明还涉及一种结合分子，包括至少两个单一可变抗体结构域，每个结构域靶向上述纤维化效应细胞上的一个受体。本发明还涉及编码这种结合分子的核酸，表达这种结合分子的宿主细胞以及制备这种结合分子的方法。本发明还涉及包括这种结合分子的制药组合物以及这种结合分子和/或组合物的用途，特别是用于预防、治疗或诊断目的。