1-(4-fluorobenzyl)-N5-hydroxy-N3-isopropyl-N5-methyl-1H-pyrrolo[2,3-c]pyridine-3,5-dicarboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: 1-(4-fluorobenzyl)-N5-hydroxy-N3-isopropyl-N5-methyl-1H-pyrrolo[2,3-c]pyridine-3,5-dicarboxamide
• 英文别名: 1-[(4-fluorophenyl)methyl]-N5-hydroxy-N3-isopropyl-N5-methyl-pyrrolo[2,3-c]pyridine-3,5-dicarboxamide；1-[(4-fluorophenyl)methyl]-5-N-hydroxy-5-N-methyl-3-N-propan-2-ylpyrrolo[2,3-c]pyridine-3,5-dicarboxamide
• 化学式: C₂₀H₂₁FN₄O₃
• 分子量: 384.41
• InChiKey: WYNOLTYCXPPBAP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  87.5
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  methyl 1-(4-fluorobenzyl)-3-(isopropylcarbamoyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate 、 N-甲基羟胺盐酸盐 在 sodium tert-pentoxide 作用下， 以 N-甲基吡咯烷酮 为溶剂， 以62%的产率得到1-(4-fluorobenzyl)-N5-hydroxy-N3-isopropyl-N5-methyl-1H-pyrrolo[2,3-c]pyridine-3,5-dicarboxamide
  参考文献：
  名称：

  Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK

  摘要：

  HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the beta-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.10.022

文献信息

• INHIBITORS OF THE HIV INTEGRASE ENZYME
  申请人：Dress Klaus Ruprecht

  公开号：US20090170846A1

  公开（公告）日：2009-07-02

  The present invention is directed to compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, their synthesis, and their use as modulators or inhibitors of the human immunodeficiency virus “HIV” integrase enzyme. Formula (I).

  本发明涉及公式（I）的化合物，以及其制备的药用可接受的盐和溶剂，以及它们作为人类免疫缺陷病毒“HIV”整合酶酶的调节剂或抑制剂的用途。公式（I）。
• [EN] INHIBITORS OF THE HIV INTEGRASE ENZYME<br/>[FR] INHIBITEURS DE L'ENZYME INTÉGRASE DU VIH
  申请人：PFIZER PROD INC

  公开号：WO2007039802A1

  公开（公告）日：2007-04-12

  [EN] The present invention is directed to compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, their synthesis, and their use as modulators or inhibitors of the human immunodeficienc virus "HIV" inte rase enzyme. Formula (I).
  [FR] La présente invention concerne des composés de formule (I) et des sels acceptables pharmaceutiquement et des solvates associés, ainsi que leur synthèse et leur utilisation en tant que modulateurs ou inhibiteurs de l'enzyme intégrase du virus de l'immunodéficience humaine (VIH). Formule (I).
• Azaindole N-methyl hydroxamic acids as HIV-1 integrase inhibitors-II. The impact of physicochemical properties on ADME and PK
  作者：Steven P. Tanis、Michael B. Plewe、Ted W. Johnson、Scott L. Butler、Deepak Dalvie、Dorothy DeLisle、Klaus R. Dress、Qiyue Hu、Buwen Huang、Jon E. Kuehler、Atsuo Kuki、Wen Liu、Qinghai Peng、Graham L. Smith、Jim Solowiej、Khanh T. Tran、Hai Wang、Anle Yang、Chunfeng Yin、Xiaoming Yu、Junhu Zhang、Huichun Zhu

  DOI：10.1016/j.bmcl.2010.10.022

  日期：2010.12

  HIV-1 integrase is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the discovery of azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. N-Methyl hydroxamic acids were stable against oxidative metabolism, however were cleared rapidly through phase 2 glucuronidation pathways. We were able to introduce polar groups at the beta-position of the azaindole core thereby altering physical properties by lowering calculated log D values (c Log D) which resulted in attenuated clearance rates in human hepatocytes. Pharmacokinetic data in dog for representative compounds demonstrated moderate oral bioavailability and reasonable half-lives. These ends were accomplished without a large negative impact on enzymatic and antiviral activity, thus suggesting opportunities to alter clearance parameters in future series. (C) 2010 Elsevier Ltd. All rights reserved.