N¹-(5-(2-(6-amino-4-methylpyridin-2-yl)ethyl)pyridin-3-yl)-N¹,N²-dimethylethane-1,2-diamine

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: N¹-(5-(2-(6-amino-4-methylpyridin-2-yl)ethyl)pyridin-3-yl)-N¹,N²-dimethylethane-1,2-diamine
• 英文别名: N1-(5-(2-(6-Amino-4-Methylpyridin-2-Yl)ethyl)pyridin-3-Yl)-N1,N2-Dimethylethane-1,2-Diamine；N'-[5-[2-(6-amino-4-methylpyridin-2-yl)ethyl]pyridin-3-yl]-N,N'-dimethylethane-1,2-diamine
• 化学式: C₁₇H₂₅N₅
• 分子量: 299.419
• InChiKey: BAILAIZRWKFZJT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  67.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-溴-5-(溴甲基)吡啶 在 tris-(dibenzylideneacetone)dipalladium(0) 、 正丁基锂 、 盐酸羟胺 、 sodium t-butanolate 、 2-二环己膦基-2'-(N,N-二甲胺)-联苯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 正己烷 、 水 为溶剂， 反应 1.33h， 生成 N¹-(5-(2-(6-amino-4-methylpyridin-2-yl)ethyl)pyridin-3-yl)-N¹,N²-dimethylethane-1,2-diamine
  参考文献：
  名称：

  2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity

  摘要：

  We have analyzed a recently obtained crystal structure of human neuronal nitric Oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and tat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and, conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected) inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits K-i values of 24 and SS nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.

  DOI：

  10.1021/acs.jmedchem.5b00573

文献信息

• Mammalian and Bacterial Nitric Oxide Synthase Inhibitors
  申请人：Northwestern University

  公开号：US20160122302A1

  公开（公告）日：2016-05-05

  Compounds and related methods for inhibition of mammalian and bacterial nitric oxide synthase.

  化合物及相关方法，用于抑制哺乳动物和细菌的一氧化氮合酶。
• Mammalian and bacterial nitric oxide synthase inhibitors
  申请人：Northwestern University

  公开号：US10759791B2

  公开（公告）日：2020-09-01

  Disclosed are compounds that are shown to inhibit the biological activity of nitric oxide synthases (NOSs). Also disclosed are pharmaceutical compositions comprising the compounds, and methods of using the compounds and pharmaceutical compositions for treating a subject in need thereof. Because the disclosed compounds are shown to inhibit the activity of nitric oxide synthases (NOSs), the disclosed compounds and pharmaceutical compositions may be utilized in methods for treating a subject having or at risk for developing a disease or disorder that is associated with NOS activity.

  所公开的化合物被证明可抑制一氧化氮合酶（NOSs）的生物活性。还公开了包含这些化合物的药物组合物，以及使用这些化合物和药物组合物治疗有需要的受试者的方法。由于所公开的化合物被证明可抑制一氧化氮合酶（NOSs）的活性，因此所公开的化合物和药物组合物可用于治疗患有或有可能患有与 NOS 活性相关的疾病或紊乱的受试者的方法中。
• US9951014B2
  申请人：——

  公开号：US9951014B2

  公开（公告）日：2018-04-24
• 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity
  作者：Soosung Kang、Huiying Li、Wei Tang、Pavel Martásek、Linda J. Roman、Thomas L. Poulos、Richard B. Silverman

  DOI：10.1021/acs.jmedchem.5b00573

  日期：2015.7.23

  We have analyzed a recently obtained crystal structure of human neuronal nitric Oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and tat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and, conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected) inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits K-i values of 24 and SS nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.