Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC inhibitors: Discovery of TP0586532

  • Bioorg Med Chem. 2021 Jan 15;30:115964. doi: 10.1016/j.bmc.2020.115964.
Fumihito Ushiyama  1 ,  Hajime Takashima  2 ,  Yohei Matsuda  2 ,  Yuya Ogata  2 ,  Naoki Sasamoto  2 ,  Risa Kurimoto-Tsuruta  2 ,  Kaori Ueki  2 ,  Nozomi Tanaka-Yamamoto  2 ,  Mayumi Endo  2 ,  Masashi Mima  2 ,  Kiyoko Fujita  2 ,  Iichiro Takata  2 ,  Satoshi Tsuji  2 ,  Haruhiro Yamashita  2 ,  Hirotoshi Okumura  2 ,  Katsumasa Otake  2 ,  Hiroyuki Sugiyama  2
Affiliations
  • 1. Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-Cho, Kita-Ku, Saitama 331-9530, Japan. Electronic address: [email protected].
  • 2. Taisho Pharmaceutical Co., Ltd, 1-403 Yoshino-Cho, Kita-Ku, Saitama 331-9530, Japan.
PMID: 33385955 DOI: 10.1016/j.bmc.2020.115964
Abstract

Infectious diseases caused by resistant Gram-negative bacteria have become a serious problem, and the development of therapeutic drugs with a novel mechanism of action and that do not exhibit cross-resistance with existing drugs has been earnestly desired. UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a drug target that has been studied for a long time. However, no LpxC inhibitors are available on the market at present. In this study, we sought to create a new Antibacterial agent without a hydroxamate moiety, which is a common component of the major LpxC inhibitors that have been reported to date and that may cause toxicity. As a result, a development candidate, TP0586532, was created that is effective against carbapenem-resistant Klebsiella pneumoniae and does not pose a cardiovascular risk.

Keywords
Antibacterial agent; Gram-negative bacteria; Lead optimization; LpxC; Non-hydroxamate; carbapenem-resistant Enterobacteriaceae.
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