MMV689244 | 1486506-92-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: MMV689244
• 英文别名: EPL-BS1246；(S)-2-(4-Chlorophenyl)-2-Pyridin-3-Yl-1-[4-[4-(Trifluoromethyl)phenyl]piperazin-1-Yl]ethanone；(2S)-2-(4-chlorophenyl)-2-pyridin-3-yl-1-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]ethanone
• CAS: 1486506-92-6
• 化学式: C₂₄H₂₁ClF₃N₃O
• 分子量: 459.898
• InChiKey: OJFZYAQGMWSUID-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.23
• 重原子数：
  32.0
• 可旋转键数：
  4.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  36.44
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为产物：
  描述：

  2-(4-chlorophenyl)-1-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}-2-(pyridin-3-yl)ethanone 生成 MMV689244
  参考文献：
  名称：

  Complexes of Trypanosoma cruzi Sterol 14α-Demethylase (CYP51) with Two Pyridine-based Drug Candidates for Chagas Disease

  摘要：

  Chagas disease, caused by the eukaryotic (protozoan) parasite Trypanosoma cruzi, is an alarming emerging global health problem with no clinical drugs available to treat the chronic stage. Azole inhibitors of sterol 14 alpha-demethylase (CYP51) were proven effective against Chagas, and antifungal drugs posaconazole and ravuconazole have entered clinical trials in Spain, Bolivia, and Argentina. Here we present the x-ray structures of T. cruzi CYP51 in complexes with two alternative drug candidates, pyridine derivatives (S)-(4-chlorophenyl)-1-(4-(4-(trifluoromethyl)phenyl)-piperazin-1-yl)-2-(pyridin-3-yl)ethanone (UDO; Protein Data Bank code 3ZG2) and N-[4-(trifluoromethyl)phenyl]-N-[1-[5-(trifluoromethyl)-2-pyridyl]-4-piperidyl]pyridin-3-amine (UDD; Protein Data Bank code 3ZG3). These compounds have been developed by the Drugs for Neglected Diseases initiative (DNDi) and are highly promising antichagasic agents in both cellular and in vivo experiments. The binding parameters and inhibitory effects on sterol 14 alpha-demethylase activity in reconstituted enzyme reactions confirmed UDO and UDD as potent and selective T. cruzi CYP51 inhibitors. Comparative analysis of the pyridine-and azole-bound CYP51 structures uncovered the features that make UDO and UDD T. cruzi CYP51-specific. The structures suggest that although a precise fit between the shape of the inhibitor molecules and T. cruzi CYP51 active site topology underlies their high inhibitory potency, a longer coordination bond between the catalytic heme iron and the pyridine nitrogen implies a weaker influence of pyridines on the iron reduction potential, which may be the basis for the observed selectivity of these compounds toward the target enzyme versus other cytochrome P450s, including human drug-metabolizing P450s. These findings may pave the way for the development of novel CYP51-targeted drugs with optimized metabolic properties that are very much needed for the treatment of human infections caused by eukaryotic microbial pathogens.

  DOI：

  10.1074/jbc.m113.497990

文献信息

• Two Analogues of Fenarimol Show Curative Activity in an Experimental Model of Chagas Disease
  作者：Martine Keenan、Jason H. Chaplin、Paul W. Alexander、Michael J. Abbott、Wayne M. Best、Andrea Khong、Adriana Botero、Catherine Perez、Scott Cornwall、R. Andrew Thompson、Karen L. White、David M. Shackleford、Maria Koltun、Francis C. K. Chiu、Julia Morizzi、Eileen Ryan、Michael Campbell、Thomas W. von Geldern、Ivan Scandale、Eric Chatelain、Susan A. Charman

  DOI：10.1021/jm401610c

  日期：2013.12.27

  Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.
• Complexes of Trypanosoma cruzi Sterol 14α-Demethylase (CYP51) with Two Pyridine-based Drug Candidates for Chagas Disease
  作者：Tatiana Y. Hargrove、Zdzislaw Wawrzak、Paul W. Alexander、Jason H. Chaplin、Martine Keenan、Susan A. Charman、Catherine J. Perez、Michael R. Waterman、Eric Chatelain、Galina I. Lepesheva

  DOI：10.1074/jbc.m113.497990

  日期：2013.11

  Chagas disease, caused by the eukaryotic (protozoan) parasite Trypanosoma cruzi, is an alarming emerging global health problem with no clinical drugs available to treat the chronic stage. Azole inhibitors of sterol 14 alpha-demethylase (CYP51) were proven effective against Chagas, and antifungal drugs posaconazole and ravuconazole have entered clinical trials in Spain, Bolivia, and Argentina. Here we present the x-ray structures of T. cruzi CYP51 in complexes with two alternative drug candidates, pyridine derivatives (S)-(4-chlorophenyl)-1-(4-(4-(trifluoromethyl)phenyl)-piperazin-1-yl)-2-(pyridin-3-yl)ethanone (UDO; Protein Data Bank code 3ZG2) and N-[4-(trifluoromethyl)phenyl]-N-[1-[5-(trifluoromethyl)-2-pyridyl]-4-piperidyl]pyridin-3-amine (UDD; Protein Data Bank code 3ZG3). These compounds have been developed by the Drugs for Neglected Diseases initiative (DNDi) and are highly promising antichagasic agents in both cellular and in vivo experiments. The binding parameters and inhibitory effects on sterol 14 alpha-demethylase activity in reconstituted enzyme reactions confirmed UDO and UDD as potent and selective T. cruzi CYP51 inhibitors. Comparative analysis of the pyridine-and azole-bound CYP51 structures uncovered the features that make UDO and UDD T. cruzi CYP51-specific. The structures suggest that although a precise fit between the shape of the inhibitor molecules and T. cruzi CYP51 active site topology underlies their high inhibitory potency, a longer coordination bond between the catalytic heme iron and the pyridine nitrogen implies a weaker influence of pyridines on the iron reduction potential, which may be the basis for the observed selectivity of these compounds toward the target enzyme versus other cytochrome P450s, including human drug-metabolizing P450s. These findings may pave the way for the development of novel CYP51-targeted drugs with optimized metabolic properties that are very much needed for the treatment of human infections caused by eukaryotic microbial pathogens.