2-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)benzo[d]thiazole-7-carboxylic acid | 1224465-23-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: 2-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)benzo[d]thiazole-7-carboxylic acid
• 英文别名: 2-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl]-1,3-benzothiazole-7-carboxylic acid
• CAS: 1224465-23-9
• 化学式: C₂₈H₁₉Cl₂N₅O₄S
• 分子量: 592.462
• InChiKey: VUXOQFRVHLWQSW-RBTNQOKQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  40
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  146
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  methyl 2-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)benzo[d]thiazole-7-carboxylate 在 lithium chloride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以0.011 g的产率得到2-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)benzo[d]thiazole-7-carboxylic acid
  参考文献：
  名称：

  Small Molecule Antagonist of Leukocyte Function Associated Antigen-1 (LFA-1): Structure−Activity Relationships Leading to the Identification of 6-((5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic Acid (BMS-688521)

  摘要：

  Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3, 5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.

  DOI：

  10.1021/jm100348u

文献信息

• Small Molecule Antagonist of Leukocyte Function Associated Antigen-1 (LFA-1): Structure−Activity Relationships Leading to the Identification of 6-((5<i>S</i>,9<i>R</i>)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)nicotinic Acid (BMS-688521)
  作者：Scott H. Watterson、Zili Xiao、Dharmpal S. Dodd、David R. Tortolani、Wayne Vaccaro、Dominique Potin、Michele Launay、Dawn K. Stetsko、Stacey Skala、Patric M. Davis、Deborah Lee、Xiaoxia Yang、Kim W. McIntyre、Praveen Balimane、Karishma Patel、Zheng Yang、Punit Marathe、Pathanjali Kadiyala、Andrew J. Tebben、Steven Sheriff、ChiehYing Y. Chang、Theresa Ziemba、Huiping Zhang、Bang-Chi Chen、Albert J. DelMonte、Nelly Aranibar、Murray McKinnon、Joel C. Barrish、Suzanne J. Suchard、T. G. Murali Dhar

  DOI：10.1021/jm100348u

  日期：2010.5.13

  Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3, 5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.