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


Bioorganic & Medicinal Chemistry


Fumihito Ushiyama, Hajime Takashima, Yohei Matsuda, Yuya Ogata, Naoki Sasamoto, Risa Kurimoto-Tsuruta, Kaori Ueki, Nozomi Tanaka-Yamamoto, Mayumi Endo, Masashi Mima, Kiyoko Fujita, Iichiro Takata, Satoshi Tsuji, Haruhiro Yamashita Hirotoshi, Okumura Katsumasa, Otake, Hiroyuki Sugiyama



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.

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