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

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

Rebalancing Hydrogenation and Dehydration Performances for Efficient Hydrodeoxygenation of Biomass Derivatives to Match Reaction Temperature-Induced Rate-Determining Step Switch

For reactions with multielementary steps, typically hydrodeoxygenation (HDO), balancing the reaction rate of each step (hydrogenation and dehydration) is crucial to speed up the overall process. However, reaction-condition-induced rate-determining step switch has long been overlooked and misleads our configuration of active sites. In this work, a relay catalysis of PtFe5/WOx and Pt/WOx is applied to facilitate the whole HDO process, in which bimetallic PtFe5/WOx catalyst boosts the hydrogenation step by promoting the adsorption of oxygen-containing intermediates at high temperatures via the oxophilic Fe species and Pt/WOx with more W–OH–W Brønsted acid sites (BAS) facilitates the deoxygenation activity. By balancing hydrogenation and dehydration performances, the relay catalysis system achieves a turnover frequency of 671.5 h–1 in the HDO of m-cresol, 3–18 times higher than that of most reported catalysts. This finding offers caution to the catalyst design based on reaction conditions for reactions with multielementary steps