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 KIM in the pathogenesis of acute paricreatitis (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 requited in AP. We have identified and optimized a novel series of high affinity KIM inhibitors with favorable physicochemical properties. The leading example is exquisitely selective, has low clearance in two species, prevents king and kidney damage in a rat model-of acute pancreatitis, and is progressing into preclinical development.