2-(2-(1H-benzo[d]imidazol-1-yl)-N-(3-fluorophenyl)acetamido)-N-cyclopentyl-2-o-tolylacetamide | 1355446-05-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-(2-(1H-benzo[d]imidazol-1-yl)-N-(3-fluorophenyl)acetamido)-N-cyclopentyl-2-o-tolylacetamide
• 英文别名: 2-(N-[2-(benzimidazol-1-yl)acetyl]-3-fluoroanilino)-N-cyclopentyl-2-(2-methylphenyl)acetamide；ML309；rac-ML309
• CAS: 1355446-05-7
• 化学式: C₂₉H₂₉FN₄O₂
• 分子量: 484.573
• InChiKey: GZLNOSRHZLTDMT-UHFFFAOYSA-N

物化性质

• 密度：
  1.26±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  36
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  67.2
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(2-(1H-benzo[d]imidazol-1-yl)-N-(3-fluorophenyl)acetamido)-N-cyclopentyl-2-o-tolylacetamide 在 Chiralcel OD column 作用下， 以73 mg的产率得到(R)-2-(2-(1H-benzo[d]imidazol-1-yl)-N-(3-fluorophenyl)acetamido)-N-cyclopentyl-2-o-tolylacetamide
  参考文献：
  名称：

  Biochemical, Cellular, and Biophysical Characterization of a Potent Inhibitor of Mutant Isocitrate Dehydrogenase IDH1

  摘要：

  Background: IDH1 R132H, implicated in glioblastoma and AML, produces the oncometabolite 2-HG. Results: A detailed binding mechanism of a small molecule inhibitor (ML309) is proposed. Conclusion: ML309 competes with -KG but is uncompetitive with NADPH and rapidly and reversibly affects cellular 2-HG levels. Significance: Understanding IDH1 R132H inhibition sets the stage for targeting IDH1 R132H for the treatment of cancer.Two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases. In this study, we investigated the mechanism of action of a newly discovered inhibitor, ML309, using biochemical, cellular, and biophysical approaches. Substrate binding and product inhibition studies helped to further elucidate the IDH1 R132H catalytic cycle. This rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active (IC50 = 68 nm), whereas the (-) isomer is over 400-fold less active (IC50 = 29 m) for IDH1 R132H inhibition. IDH1 R132C was similarly inhibited by (+)-ML309. WT IDH1 was largely unaffected by (+)-ML309 (IC50 >36 m). Kinetic analyses combined with microscale thermophoresis and surface plasmon resonance indicate that this reversible inhibitor binds to IDH1 R132H competitively with respect to -ketoglutarate and uncompetitively with respect to NADPH. A reaction scheme for IDH1 R132H inhibition by ML309 is proposed in which ML309 binds to IDH1 R132H after formation of the IDH1 R132H NADPH complex. ML309 was also able to inhibit 2-HG production in a glioblastoma cell line (IC50 = 250 nm) and had minimal cytotoxicity. In the presence of racemic ML309, 2-HG levels drop rapidly. This drop was sustained until 48 h, at which point the compound was washed out and 2-HG levels recovered.

  DOI：

  10.1074/jbc.m113.511030
• 作为产物：
  描述：

  3-氟苯胺 、 苯并咪唑-1-乙酸 、 环戊异腈 、 2-甲基苯甲醛 以 甲醇 为溶剂， 反应 4.0h， 以22%的产率得到2-(2-(1H-benzo[d]imidazol-1-yl)-N-(3-fluorophenyl)acetamido)-N-cyclopentyl-2-o-tolylacetamide
  参考文献：
  名称：

  Biochemical, Cellular, and Biophysical Characterization of a Potent Inhibitor of Mutant Isocitrate Dehydrogenase IDH1

  摘要：

  Background: IDH1 R132H, implicated in glioblastoma and AML, produces the oncometabolite 2-HG. Results: A detailed binding mechanism of a small molecule inhibitor (ML309) is proposed. Conclusion: ML309 competes with -KG but is uncompetitive with NADPH and rapidly and reversibly affects cellular 2-HG levels. Significance: Understanding IDH1 R132H inhibition sets the stage for targeting IDH1 R132H for the treatment of cancer.Two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases. In this study, we investigated the mechanism of action of a newly discovered inhibitor, ML309, using biochemical, cellular, and biophysical approaches. Substrate binding and product inhibition studies helped to further elucidate the IDH1 R132H catalytic cycle. This rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active (IC50 = 68 nm), whereas the (-) isomer is over 400-fold less active (IC50 = 29 m) for IDH1 R132H inhibition. IDH1 R132C was similarly inhibited by (+)-ML309. WT IDH1 was largely unaffected by (+)-ML309 (IC50 >36 m). Kinetic analyses combined with microscale thermophoresis and surface plasmon resonance indicate that this reversible inhibitor binds to IDH1 R132H competitively with respect to -ketoglutarate and uncompetitively with respect to NADPH. A reaction scheme for IDH1 R132H inhibition by ML309 is proposed in which ML309 binds to IDH1 R132H after formation of the IDH1 R132H NADPH complex. ML309 was also able to inhibit 2-HG production in a glioblastoma cell line (IC50 = 250 nm) and had minimal cytotoxicity. In the presence of racemic ML309, 2-HG levels drop rapidly. This drop was sustained until 48 h, at which point the compound was washed out and 2-HG levels recovered.

  DOI：

  10.1074/jbc.m113.511030

文献信息

• THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHODS OF USE
  申请人：Popovici-Muller Janeta

  公开号：US20130184222A1

  公开（公告）日：2013-07-18

  Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1 comprising administering to a subject in need thereof a compound described here.

  提供了一种治疗癌症的方法，其特征在于存在IDH1基因突变等位基因，包括向需要此类治疗的受试者施用此处所述的化合物。
• [EN] MODULATORS OF ARALAR FOR TREATING NEUROLOGICAL DISORDERS<br/>[FR] MODULATEURS D'ARALAR POUR LE TRAITEMENT DE TROUBLES NEUROLOGIQUES
  申请人：UNIV LAUSANNE

  公开号：WO2021176098A1

  公开（公告）日：2021-09-10

  The present invention relates to compounds or pharmaceutical compositions for treating neurological disorders. In particular, the invention relates to a modulator of gamma- Aminobutyric acid (GABA) signaling for use in treating a neurological disorder in a subject with Cyfipl haploinsufficiency. Furthermore, the present invention relates to a modulator of Aralar for use in treating a neurological disorder. The invention further relates to non-medical uses of the compounds or compositions of the invention. Furthermore, the invention relates to a method for identifying a modulator of Aralar and/or a neuroactive drug.
• Biochemical, Cellular, and Biophysical Characterization of a Potent Inhibitor of Mutant Isocitrate Dehydrogenase IDH1
  作者：Mindy I. Davis、Stefan Gross、Min Shen、Kimberly S. Straley、Rajan Pragani、Wendy A. Lea、Janeta Popovici-Muller、Byron DeLaBarre、Erin Artin、Natasha Thorne、Douglas S. Auld、Zhuyin Li、Lenny Dang、Matthew B. Boxer、Anton Simeonov

  DOI：10.1074/jbc.m113.511030

  日期：2014.5

  Background: IDH1 R132H, implicated in glioblastoma and AML, produces the oncometabolite 2-HG. Results: A detailed binding mechanism of a small molecule inhibitor (ML309) is proposed. Conclusion: ML309 competes with -KG but is uncompetitive with NADPH and rapidly and reversibly affects cellular 2-HG levels. Significance: Understanding IDH1 R132H inhibition sets the stage for targeting IDH1 R132H for the treatment of cancer.Two mutant forms (R132H and R132C) of isocitrate dehydrogenase 1 (IDH1) have been associated with a number of cancers including glioblastoma and acute myeloid leukemia. These mutations confer a neomorphic activity of 2-hydroxyglutarate (2-HG) production, and 2-HG has previously been implicated as an oncometabolite. Inhibitors of mutant IDH1 can potentially be used to treat these diseases. In this study, we investigated the mechanism of action of a newly discovered inhibitor, ML309, using biochemical, cellular, and biophysical approaches. Substrate binding and product inhibition studies helped to further elucidate the IDH1 R132H catalytic cycle. This rapidly equilibrating inhibitor is active in both biochemical and cellular assays. The (+) isomer is active (IC50 = 68 nm), whereas the (-) isomer is over 400-fold less active (IC50 = 29 m) for IDH1 R132H inhibition. IDH1 R132C was similarly inhibited by (+)-ML309. WT IDH1 was largely unaffected by (+)-ML309 (IC50 >36 m). Kinetic analyses combined with microscale thermophoresis and surface plasmon resonance indicate that this reversible inhibitor binds to IDH1 R132H competitively with respect to -ketoglutarate and uncompetitively with respect to NADPH. A reaction scheme for IDH1 R132H inhibition by ML309 is proposed in which ML309 binds to IDH1 R132H after formation of the IDH1 R132H NADPH complex. ML309 was also able to inhibit 2-HG production in a glioblastoma cell line (IC50 = 250 nm) and had minimal cytotoxicity. In the presence of racemic ML309, 2-HG levels drop rapidly. This drop was sustained until 48 h, at which point the compound was washed out and 2-HG levels recovered.