N-cyclopropyl-5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)thiophene-2-carboxamide | 1254834-91-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: N-cyclopropyl-5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)thiophene-2-carboxamide
• 英文别名: 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide；Genz-669178；5-(4-Cyano-2-Methyl-1h-Benzimidazol-1-Yl)-N-Cyclopropylthiophene-2-Carboxamide；5-(4-cyano-2-methylbenzimidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide
• CAS: 1254834-91-7
• 化学式: C₁₇H₁₄N₄OS
• 分子量: 322.39
• InChiKey: XRXYHTFKWSMTFI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  99
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-溴-6-氟硝基苯 在 盐酸 、 6-chloro-3-((dimethylamino)(dimethyliminio)methyl)-1H-benzo[d][1,2,3]triazol-3-ium-1-olatehexafluorophosphate(V) 、 水 、 N,N,N-三乙基-1-丁烷铵氯化物 、 N,N-二异丙基乙胺 、 tin(ll) chloride 、 potassium hydroxide 、 lithium hydroxide 作用下， 以 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.5h， 生成 N-cyclopropyl-5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)thiophene-2-carboxamide
  参考文献：
  名称：

  Optimization of Potent Inhibitors of P. falciparum Dihydroorotate Dehydrogenase for the Treatment of Malaria

  摘要：

  Inhibition of dihydroorotate dehydrogenase (DHODH) for P. falciparum potentially represents a new treatment option for malaria, since DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and P. falciparum is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. We report herein the synthesis and structure-activity relationship of a series of 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides that are potent inhibitors against PfDHODH but do not inhibit the human enzyme. On the basis of efficacy observed in three mouse models of malaria, acceptable safety pharmacology risk assessment and safety toxicology profile in rodents, lack of potential drug-drug interactions, acceptable ADME/pharmacokinetic profile, and projected human dose, 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide 2q was identified as a potential drug development candidate.

  DOI：

  10.1021/ml200143c

文献信息

• Pyrazole derivatives as dihydroorotate dehydrogenase (DHODH) inhibitors
  申请人：INSTITUT PASTEUR

  公开号：EP2929883A1

  公开（公告）日：2015-10-14

  The present invention relates to compounds of formula (I) for their use in the treatment and/or prevention of auto-immune or auto-immune related diseases, cancer, viral infections, and central nervous system diseases and disorders, by inhibiting human dehydroorate dehydrogenase (DHODH): Wherein R1, R2, R3, R4 and Ar are as defined in claim 1.

  本发明涉及式（I）化合物，通过抑制人脱氢脱氢酶（DHODH），用于治疗和/或预防自身免疫或自身免疫相关疾病、癌症、病毒感染以及中枢神经系统疾病和失调： 其中 R1、R2、R3、R4 和 Ar 如权利要求 1 所定义。
• Optimization of Potent Inhibitors of <i>P. falciparum</i> Dihydroorotate Dehydrogenase for the Treatment of Malaria
  作者：Renato T. Skerlj、Cecilia M. Bastos、Michael L. Booker、Martin L. Kramer、Robert H. Barker、Cassandra A. Celatka、Thomas J. O’Shea、Benito Munoz、Amar Bir Sidhu、Joseph F. Cortese、Sergio Wittlin、Petros Papastogiannidis、Inigo Angulo-Barturen、Maria Belen Jimenez-Diaz、Edmund Sybertz

  DOI：10.1021/ml200143c

  日期：2011.9.8

  Inhibition of dihydroorotate dehydrogenase (DHODH) for P. falciparum potentially represents a new treatment option for malaria, since DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and P. falciparum is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. We report herein the synthesis and structure-activity relationship of a series of 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides that are potent inhibitors against PfDHODH but do not inhibit the human enzyme. On the basis of efficacy observed in three mouse models of malaria, acceptable safety pharmacology risk assessment and safety toxicology profile in rodents, lack of potential drug-drug interactions, acceptable ADME/pharmacokinetic profile, and projected human dose, 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide 2q was identified as a potential drug development candidate.