Journal of Medicinal Chemistry p. 3383 - 3404 (2017)
Update date:2022-08-17
Topics:
Walker, Ann L.
Ancellin, Nicolas
Beaufils, Benjamin
Bergeal, Marylise
Binnie, Margaret
Bouillot, Anne
Clapham, David
Denis, Alexis
Haslam, Carl P.
Holmes, Duncan S.
Hutchinson, Jonathan P.
Liddle, John
McBride, Andrew
Mirguet, Olivier
Mowat, Christopher G.
Rowland, Paul
Tiberghien, Nathalie
Trottet, Lionel
Uings, Iain
Webster, Scott P.
Zheng, Xiaozhong
Mole, Damian J.
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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