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

Vincent Sandanayaka, Bjorn Mamat, Rama K. Mishra, Jennifer Winger, Michael Krohn, Li Ming Zhou, Monica Keyvan, Livia Enache, David Sullins, Emmanuel Onua, Jun Zhang, Gudrun Halldorsdottir, Heida Sigthorsdottir, Audur Thorlaksdottir, Gudmundur Sigthorsson, Margret Thorsteinnsdottir, Douglas R. Davies, Lance J. Stewart, David E. Zembower, Thorkell AndressonAlex S. Kiselyov, Jasbir Singh, Mark E. Gurney

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA4H) as a key target for the treatment of cardiovascular disease. We combined fragmentbased crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA4H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA4H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (Kd=26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.

Original languageEnglish (US)
Pages (from-to)573-585
Number of pages13
JournalJournal of Medicinal Chemistry
Volume53
Issue number2
DOIs
StatePublished - Mar 1 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Sandanayaka, V., Mamat, B., Mishra, R. K., Winger, J., Krohn, M., Zhou, L. M., Keyvan, M., Enache, L., Sullins, D., Onua, E., Zhang, J., Halldorsdottir, G., Sigthorsdottir, H., Thorlaksdottir, A., Sigthorsson, G., Thorsteinnsdottir, M., Davies, D. R., Stewart, L. J., Zembower, D. E., ... Gurney, M. E. (2010). 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. Journal of Medicinal Chemistry, 53(2), 573-585. https://doi.org/10.1021/jm900838g