N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)picolinamide | 1218926-17-0

• 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: N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)picolinamide
• 英文别名: N-[3-chloro-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]pyridine-2-carboxamide；N-(3-chloro-4-phthalimido-phenyl)picolinamide；N-[3-chloro-4-(1,3-dioxoisoindol-2-yl)phenyl]pyridine-2-carboxamide
• CAS: 1218926-17-0
• 化学式: C₂₀H₁₂ClN₃O₃
• 分子量: 377.787
• InChiKey: BXCSFHHEMVAIFH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  79.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  N,N-二boc-2-氯-4-硝基苯胺 在 盐酸 、 5%-palladium/activated carbon 、 氢气 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙酸乙酯 、 甲苯 为溶剂， 150.0 ℃ 、101.33 kPa 条件下， 反应 25.75h， 生成 N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)picolinamide
  参考文献：
  名称：

  Discovery, Synthesis, and Structure–Activity Relationship Development of a Series of N-4-(2,5-Dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): Characterization of a Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 (mGlu₄) with Oral Efficacy in an Antiparkinsonian Animal Model

  摘要：

  There is an increasing amount of literature data showing the positive effects on preclinical antiparkinsonian rodent models with selective positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)). However, most of the data generated utilize compounds that have not been optimized for druglike properties, and as a consequence, they exhibit poor pharmacokinetic properties and thus do not cross the blood-brain barrier. Herein, we report on a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides with improved PK properties with excellent potency and selectivity as well as improved brain exposure in rodents. Finally, ML182 was shown to be orally active in the haloperidol induced catalepsy model, a well-established antiparkinsonian model.

  DOI：

  10.1021/jm200956q

文献信息

• [EN] PHTHALIMIDE DERIVATIVE METABOTROPIC GLUTAMATE R4 LIGANDS<br/>[FR] LIGANDS DU GLUTAMATE MÉTABOTROPIQUE R4 DÉRIVÉ DE PHTALAMIDE
  申请人：MERCK & CO INC

  公开号：WO2010033349A1

  公开（公告）日：2010-03-25

  Disclosed are mGluR4 positive allosteric modulator ligands of general formula (I) and radiolabeled derivates, their use as therapeutic agents for the treatment of central nervous system disorders modulated by mGluR4 and as ligands for the labeling and diagnostic imaging of mGluR4 in mammals.

  本文披露了一般式（I）的mGluR4阳性变构调节剂配体以及放射标记衍生物，它们被用作治疗中枢神经系统疾病的治疗剂，这些疾病受mGluR4调节，并且作为哺乳动物中mGluR4的标记和诊断成像的配体。
• PHTHALIMIDE DERIVATIVE METABOTROPIC GLUTAMATE R4 LIGANDS
  申请人：McCauley John A.

  公开号：US20110318266A1

  公开（公告）日：2011-12-29

  Disclosed are mGluR4 positive allosteric modulator ligands of general formula (I) and radiolabeled derivates, their use as therapeutic agents for the treatment of central nervous system disorders modulated by mGluR4 and as ligands for the labeling and diagnostic imaging of mGluR4 in mammals.

  本发明揭示了通式（I）的mGluR4阳性变构调节剂配体和放射性标记衍生物，它们可作为治疗中枢神经系统疾病的治疗剂，这些疾病受mGluR4调节，同时也可作为哺乳动物体内mGluR4的标记和诊断成像的配体。
• Chemical Modulation of Mutant mGlu₁ Receptors Derived from Deleterious <i>GRM1</i> Mutations Found in Schizophrenics
  作者：Hyekyung P. Cho、Pedro M. Garcia-Barrantes、John T. Brogan、Corey R. Hopkins、Colleen M. Niswender、Alice L. Rodriguez、Daryl F. Venable、Ryan D. Morrison、Michael Bubser、J. Scott Daniels、Carrie K. Jones、P. Jeffrey Conn、Craig W. Lindsley

  DOI：10.1021/cb500560h

  日期：2014.10.17

  Schizophrenia is a complex and highly heterogeneous psychiatric disorder whose precise etiology remains elusive. While genome-wide association studies (GWAS) have identified risk genes, they have failed to determine if rare coding single nucleotide polymorphisms (nsSNPs) contribute in schizophrenia. Recently, two independent studies identified 12 rare, deleterious nsSNPS in the GRM1 gene, which encodes the metabotropic glutamate receptor subtype 1 (mGlu(1)), in schizophrenic patients. Here, we generated stable cell lines expressing the mGlu(1) mutant receptors and assessed their pharmacology. Using both the endogenous agonist glutamate and the synthetic agonist DHPG, we found that several of the mutant mGlu(1) receptors displayed a loss of function that was not due to a loss in plasma membrane expression. Due to a lack of mGlu(1) positive allosteric modulators (PAM) tool compounds active at human mGlu(1), we optimized a known mGlu4 PAM/mGlu(1) NAM chemotype into a series of potent and selective mGlu(1) PAMs by virtue of a double "molecular switch". Employing mGlu(1) PAMs from multiple chemotypes, we demonstrate that the mutant receptors can be potentiated by small molecules and in some cases efficacy restored to that comparable to wild type mGlu(1) receptors, suggesting deficits in patients with schizophrenia due to these mutations may be amenable to intervention with an mGlu(1) PAM. However, in wild type animals, mGlu(1) negative allosteric modulators (NAMs) are efficacious in classic models predictive of antipsychotic activity, whereas we show that mGlu(1) PAMs have no effect to slight potentiation in these models. These data further highlight the heterogeneity of schizophrenia and the critical role of patient selection strategies in psychiatric clinical trials to match genotype with therapeutic mechanism.