title: Development of a Series of Kynurenine 3-Monooxygenase Inhibitors Leading to a Clinical Candidate for the Treatment of Acute Pancreatitis.
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.
authors.affiliation: Discovery Partnerships with Academia, GlaxoSmithKline , Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: Ann L
authors.identifier: 0000-0002-1027-2099
authors.initials: AL
authors.lastname: Walker
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline , Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ancellin
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline , Paris, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Beaufils
authors.affiliation: Platform Technology Sciences, GlaxoSmithKline Stevenage SG1 2NY, UK.
authors.forename: Marylise
authors.initials: M
authors.lastname: Bergeal
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh , Edinburgh EH16 4TJ, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Binnie
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline , Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Bouillot
authors.affiliation: Platform Technology Sciences, GlaxoSmithKline Stevenage SG1 2NY, UK.
authors.forename: David
authors.initials: D
authors.lastname: Clapham
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline , Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Denis
authors.affiliation: Platform Technology Sciences, GlaxoSmithKline Stevenage SG1 2NY, UK.
authors.forename: Carl P
authors.initials: CP
authors.lastname: Haslam
authors.affiliation: Discovery Partnerships with Academia, GlaxoSmithKline , Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: Duncan S
authors.initials: DS
authors.lastname: Holmes
authors.affiliation: Platform Technology Sciences, GlaxoSmithKline Stevenage SG1 2NY, UK.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Hutchinson
authors.affiliation: Discovery Partnerships with Academia, GlaxoSmithKline , Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: John
authors.initials: J
authors.lastname: Liddle
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh , Edinburgh EH16 4TJ, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: McBride
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline , Paris, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Mirguet
authors.affiliation: EastChem School of Chemistry, University of Edinburgh , Edinburgh EH9 3FJ, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Mowat
authors.affiliation: Platform Technology Sciences, GlaxoSmithKline Stevenage SG1 2NY, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Rowland
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline , Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Tiberghien
authors.affiliation: Flexible Discovery Unit, GlaxoSmithKline , Paris, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Trottet
authors.affiliation: Discovery Partnerships with Academia, GlaxoSmithKline , Gunnels Wood Road, Stevenage SG1 2NY, UK.
authors.forename: Iain
authors.initials: I
authors.lastname: Uings
authors.affiliation: Centre for Cardiovascular Science, University of Edinburgh , Edinburgh EH16 4TJ, UK.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Webster
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh , Edinburgh EH16 4TJ, UK.
authors.forename: Xiaozhong
authors.initials: X
authors.lastname: Zheng
authors.affiliation: MRC Centre for Inflammation Research, University of Edinburgh , Edinburgh EH16 4TJ, UK.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Mole
mesh_terms: D000208:Acute Disease; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D050601:Kynurenine 3-Monooxygenase / Q000037:antagonists & inhibitors*; D010195:Pancreatitis / Q000188:drug therapy*; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D050601:Kynurenine 3-Monooxygenase