Discovery of 4-[(2S)-2-{[4-(4-chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis.

  title={Discovery of 4-[(2S)-2-\{[4-(4-chlorophenoxy)phenoxy]methyl\}-1-pyrrolidinyl]butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis.},
  author={Vincent Sandanayaka and Bjorn Mamat and Rama K. Mishra and Jennifer Winger and Michael Krohn and Liming Zhou and Monica Keyvan and Livia A Enache and David W Sullins and Emmanuel T Onua and Jun Yu Zhang and Gudrun V Halldorsdottir and Heida Sigthorsdottir and Audur Thorlaksdottir and Gudmundur Sigthorsson and Margret Thorsteinnsdottir and Douglas R. Davies and Lance J. Stewart and David E Zembower and Thorkell Andr{\'e}sson and Alexander Kiselyov and Jasbir Singh and Mark E Gurney},
  journal={Journal of medicinal chemistry},
  volume={53 2},
Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent… CONTINUE READING

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