LpxC inhibitors: a patent review (2010-2016)
LpxC inhibitors: a patent review (2010-2016)
复制标题
DOI：
10.1080/13543776.2017.1360282
复制
发表时间：
2017-01-01
影响因子：
6.6
通讯作者：
Holl, Ralph
中科院分区：
文献类型：
--
作者：
Kalinin, Dmitrii V.;Holl, Ralph
简介：锌离子依赖性脱乙酰酶LpxC是革兰氏阴性菌中脂质A生物合成的必需酶，并且是开发选择性对抗革兰氏阴性病原体的抗生素的有希望的靶标。本文介绍了LpxC的结构和功能，并沿着列举了几种已报道的LpxC抑制剂的结构。本文回顾了2010年至2016年期间报告的专利和关于新型小分子LpxC抑制剂的相关研究出版物。重点放在已报道的LpxC抑制剂系列中的结构-活性关系上。专家意见：对专利进行的分析表明，目前对新型LpxC抑制剂的研究重点是小分子，它们具有共同的结构特征，例如Zn 2 +-螯合基团以及高度亲脂性的侧链。然而，尽管许多报道的化合物的临床前数据很有希望，但除了最近撤回的临床候选物ACHN-975外，还没有其他LpxC抑制剂进入临床试验。临床候选物的缺乏可能与LpxC抑制剂的共同结构元件引起的不期望的作用有关。
Introduction: The Zn2+-dependent deacetylase LpxC is an essential enzyme of lipid A biosynthesis in Gram-negative bacteria and a promising target for the development of antibiotics selectively combating Gram-negative pathogens. Researchers from industry and academia have synthesized structurally diverse LpxC inhibitors, exhibiting different LpxC inhibitory and antibacterial activities.Areas covered: A brief introduction into the structure and function of LpxC, showing its suitability as antibacterial target, along with the structures of several reported LpxC inhibitors, is given. The article reviews patents (reported between 2010 and 2016) and related research publications on novel small-molecule LpxC inhibitors. Emphasis is placed on structure-activity relationships within the reported series of LpxC inhibitors.Expert opinion: The performed analysis of patents revealed that the current search for novel LpxC inhibitors is focused on small molecules, sharing common structural features like a Zn2+-chelating group as well as a highly lipophilic side-chain. However, despite the promising preclinical data of many of the reported compounds, besides the recently withdrawn clinical candidate ACHN-975, no other LpxC inhibitor has entered clinical trials. The lack of clinical candidates might be related with undesired effects caused by the common structural elements of the LpxC inhibitors.