LpxC inhibitors: a patent review (2010-2016)

ABSTRACT

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 However, despite the promising preclinical data of many of the reported compounds, besides the recently withdrawn clinical candidate ACHN-975, no other LpxC inhibitor has entered clinical trials.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.

KEYWORDS:

• LpxC
• antibiotics
• LpxC inhibitors
• lipid A biosynthesis
• structure-activity relationships

Article highlights

• Inhibitors of the Zn²⁺-dependent deacetylase LpxC are a promising class of novel antibiotics possessing a so far unexploited mechanism of action.

• The patented LpxC inhibitors share common structural features like a Zn²⁺-chelating group, facilitating an efficient binding of the inhibitors to the enzyme’s catalytic Zn²⁺-ion, as well as a lipophilic side-chain, addressing the lipophilic tunnel of LpxC.

• Among the disclosed compounds, the N-aroyl-L-threonine- and methylsulfone-based LpxC inhibitors represent the most promising classes with respect to LpxC inhibitory and antibacterial activities.

• The only clinical candidate, butadiynyl derivative ACHN-975 (21), exhibiting a subnanomolar LpxC inhibitory activity and low MIC values (≤1 μg/mL) against a wide range of Gram-negative bacteria, has failed in a phase 1 human clinical trial.

• New potent LpxC inhibitors are emerging, like the recently patented fluorinated threonine derivative LPC-058 (67), which exhibits an exceptionally low K_i (EcLpxC) value of 3.5 pM and high antibacterial activities against a range of Gram-negative pathogens.

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Declaration of interest

DV Kalinin is supported by the Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM) of the University of Münster. R Holl is supported by the German Center for Infection Research (DZIF). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded by Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM) of the University of Münster, Deutsche Forschungsgemeinschaft grant number HO 5220/2-1, Deutsches Zentrum für Infektionsforschung grant number TTU 09.707_01.