naphthalene-1-carboxylic acid ((S)-2,2-dimethyl-1-{(S)-1-[(S)-2-methyl-1-(4-sulfamoylbenzylaminooxalyl)propylcarbamoyl]ethylcarbamoyl}propyl)amide

• 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: naphthalene-1-carboxylic acid ((S)-2,2-dimethyl-1-{(S)-1-[(S)-2-methyl-1-(4-sulfamoylbenzylaminooxalyl)propylcarbamoyl]ethylcarbamoyl}propyl)amide
• 英文别名: N-[(2S)-3,3-dimethyl-1-[[(2S)-1-[[(3S)-4-methyl-1,2-dioxo-1-[(4-sulfamoylphenyl)methylamino]pentan-3-yl]amino]-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]naphthalene-1-carboxamide
• 化学式: C₃₃H₄₁N₅O₇S
• 分子量: 651.784
• InChiKey: KMPBNLSKMODTGI-IYKJZBSOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  46
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  202
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  磺胺米隆 在 N-甲基吗啉 、 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 37.0h， 生成 naphthalene-1-carboxylic acid ((S)-2,2-dimethyl-1-{(S)-1-[(S)-2-methyl-1-(4-sulfamoylbenzylaminooxalyl)propylcarbamoyl]ethylcarbamoyl}propyl)amide
  参考文献：
  名称：

  The Discovery of Potent, Selective, and Reversible Inhibitors of the House Dust Mite Peptidase Allergen Der p 1: An Innovative Approach to the Treatment of Allergic Asthma

  摘要：

  Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma.

  DOI：

  10.1021/jm501102h

文献信息

• Pyruvamide Compounds as Inhibitors of Dust Mite Group 1 Peptidase Allergen and Their Use
  申请人：Robinson Clive

  公开号：US20120322722A1

  公开（公告）日：2012-12-20

  The present invention pertains generally to the field of therapeutic compounds and more specifically to certain pyruvamide compounds of the formula (X) (for convenience, collectively referred to herein as “PVA compounds”), which, inter alia, inhibit a dust mite Group 1 peptidase allergen (e.g., Der p 1, Der f 1, Eur m 1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit a dust mite Group 1 peptidase allergen, and in the treatment of diseases and disorders that are mediated by a dust mite Group 1 peptidase allergen; that are ameliorated by the inhibition of a dust mite Group 1 peptidase allergen; asthma; rhinitis; allergic conjunctivitis; atopic dermatitis; an allergic condition which is triggered by dust mites; an allergic condition which is triggered by a dust mite Group 1 peptidase allergen; and canine atopy.

  本发明一般涉及治疗化合物领域，更具体地涉及某些丙酮酰胺化合物的公式（X）（为方便起见，以下统称为“PVA化合物”），该化合物在某些情况下抑制尘螨1组蛋白酶过敏原（例如Der p 1、Der f 1、Eur m 1）。本发明还涉及包含这种化合物的药物组合物，以及在体外和体内使用这种化合物和组合物来抑制尘螨1组蛋白酶过敏原，并用于治疗由尘螨1组蛋白酶过敏原介导的疾病和疾病，通过抑制尘螨1组蛋白酶过敏原而得到缓解的疾病和疾病；哮喘；鼻炎；过敏性结膜炎；特应性皮炎；由尘螨引发的过敏症状；由尘螨1组蛋白酶过敏原引发的过敏症状；以及犬类特应性。
• PYRUVAMIDE COMPOUNDS AS INHIBITORS OF DUST MITE GROUP 1 PEPTIDASE ALLERGEN
  申请人：St. George's Hospital Medical School

  公开号：EP2526116B1

  公开（公告）日：2015-05-13
• US8541363B2
  申请人：——

  公开号：US8541363B2

  公开（公告）日：2013-09-24
• US8637453B2
  申请人：——

  公开号：US8637453B2

  公开（公告）日：2014-01-28
• The Discovery of Potent, Selective, and Reversible Inhibitors of the House Dust Mite Peptidase Allergen Der p 1: An Innovative Approach to the Treatment of Allergic Asthma
  作者：Gary K. Newton、Trevor R. Perrior、Kerry Jenkins、Meriel R. Major、Rebekah E. Key、Mark R. Stewart、Stuart Firth-Clark、Steven M. Lloyd、Jihui Zhang、Nicola J. Francis-Newton、Jonathan P. Richardson、Jie Chen、Pei Lai、David R. Garrod、Clive Robinson

  DOI：10.1021/jm501102h

  日期：2014.11.26

  Blocking the bioactivity of allergens is conceptually attractive as a small-molecule therapy for allergic diseases but has not been attempted previously. Group 1 allergens of house dust mites (HDM) are meaningful targets in this quest because they are globally prevalent and clinically important triggers of allergic asthma. Group 1 HDM allergens are cysteine peptidases whose proteolytic activity triggers essential steps in the allergy cascade. Using the HDM allergen Der p 1 as an archetype for structure-based drug discovery, we have identified a series of novel, reversible inhibitors. Potency and selectivity were manipulated by optimizing drug interactions with enzyme binding pockets, while variation of terminal groups conferred the physicochemical and pharmacokinetic attributes required for inhaled delivery. Studies in animals challenged with the gamut of HDM allergens showed an attenuation of allergic responses by targeting just a single component, namely, Der p 1. Our findings suggest that these inhibitors may be used as novel therapies for allergic asthma.