3,4-dichloro-N-[(3S,4R)-3-(hydroxymethyl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide

• 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: 3,4-dichloro-N-[(3S,4R)-3-(hydroxymethyl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide
• 化学式: C₁₂H₁₇Cl₂N₃O₂
• 分子量: 306.192
• InChiKey: ZRILTGANNYVYJH-HTQZYQBOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  77.2
• 氢给体数：
  4
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  N-Boc-4-哌啶酮-3-甲酸甲酯 在 盐酸 、 锂硼氢 、 ammonium acetate 、 sodium cyanoborohydride 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.25h， 生成 3,4-dichloro-N-[(3S,4R)-3-(hydroxymethyl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide
  参考文献：
  名称：

  Optimization of Pyrrolamide Topoisomerase II Inhibitors Toward Identification of an Antibacterial Clinical Candidate (AZD5099)

  摘要：

  AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

  DOI：

  10.1021/jm500462x