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

  • J Med Chem. 2010 Jan 28;53(2):573-85. doi: 10.1021/jm900838g.
Vincent Sandanayaka  1 ,  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 Andresson ,  Alex S Kiselyov ,  Jasbir Singh ,  Mark E Gurney
Affiliations
  • 1. Medicinal Chemistry, deCODE Chemistry, Inc., 2501 Davey Road, Woodridge, Illinois 60517, USA.
PMID: 19950900 DOI: 10.1021/jm900838g
Abstract

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 compound 20 (DG-051) (K(d) = 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.

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