2. Academic Validation
  3. Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC inhibitors: Discovery of TP0586532

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

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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