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LpxC is a zinc metalloenzyme that catalyses the committed step in synthesis of the bacterial cell wall.  Previous studies by other companies have identified inhibitors of the enzyme based on a hydroxamic acid as the zinc chelating agent.  Some have entered clinical trials as antibiotics, but not progressed, possibly because of the liabilities of off-target effects and lack of tolerability associated with the hydroxamic acids.

A collaboration between Vernalis Research and Taisho Pharmaceuticals used fragment and structure-based discovery methods to identify novel zinc-chelators.  This is described in a recent paper in the Journal of Medicinal Chemistry (vol 63, p 14805) with the most advance lead showing good antibacterial activity on cells.  Taisho Pharmaceuticals have subsequently optimised the series to a compound which has been widely profiled for antibacterial activity and considered for clinical development.

2021-03-03T10:35:34+00:00February 2nd, 2021|