2. Academic Validation
  3. Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis

Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis

  • J Med Chem. 2017 Apr 27;60(8):3383-3404. doi: 10.1021/acs.jmedchem.7b00055.
Ann L Walker 1,  Nicolas Ancellin 2,  Benjamin Beaufils 2,  Marylise Bergeal 3,  Margaret Binnie 4,  Anne Bouillot 2,  David Clapham 3,  Alexis Denis 2,  Carl P Haslam 3,  Duncan S Holmes 1,  Jonathan P Hutchinson 3,  John Liddle 1,  Andrew McBride 4,  Olivier Mirguet 2,  Christopher G Mowat 5,  Paul Rowland 3,  Nathalie Tiberghien 2,  Lionel Trottet 2,  Iain Uings 1,  Scott P Webster 4,  Xiaozhong Zheng 6,  Damian J Mole 6
Affiliations

Affiliations

  • 1 Discovery Partnerships with Academia, GlaxoSmithKline , Gunnels Wood Road, Stevenage SG1 2NY, UK.
  • 2 Flexible Discovery Unit, GlaxoSmithKline , Paris, France.
  • 3 Platform Technology Sciences, GlaxoSmithKline Stevenage SG1 2NY, UK.
  • 4 Centre for Cardiovascular Science, University of Edinburgh , Edinburgh EH16 4TJ, UK.
  • 5 EastChem School of Chemistry, University of Edinburgh , Edinburgh EH9 3FJ, UK.
  • 6 MRC Centre for Inflammation Research, University of Edinburgh , Edinburgh EH16 4TJ, UK.
PMID: 28398044 DOI: 10.1021/acs.jmedchem.7b00055
Abstract

Recently, we reported a novel role for KMO in the pathogenesis of acute pancreatitis (AP). A number of inhibitors of kynurenine 3-monooxygenase (KMO) have previously been described as potential treatments for neurodegenerative conditions and particularly for Huntington's disease. However, the inhibitors reported to date have insufficient aqueous solubility relative to their cellular potency to be compatible with the intravenous (iv) dosing route required in AP. We have identified and optimized a novel series of high affinity KMO inhibitors with favorable physicochemical properties. The leading example is exquisitely selective, has low clearance in two species, prevents lung and kidney damage in a rat model of acute pancreatitis, and is progressing into preclinical development.

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