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

Discovery and Optimization of Potent, Selective, and <i>in Vivo</i> Efficacious 2‑Aryl Benzimidazole BCATm Inhibitors

To identify BCATm inhibitors suitable for <i>in vivo</i> study, Encoded Library Technology (ELT) was used to affinity screen a 117 million member benzimidazole based DNA encoded library, which identified an inhibitor series with both biochemical and cellular activities. Subsequent SAR studies led to the discovery of a highly potent and selective compound, 1-(3-(5-bromothiophene-2-carboxamido)­cyclohexyl)-<i>N</i>-methyl-2-(pyridin-2-yl)-1<i>H</i>-benzo­[d]­imidazole-5-carboxamide (<b>8b</b>) with much improved PK properties. X-ray structure revealed that <b>8b</b> binds to the active site of BACTm in a unique mode via multiple H-bond and van der Waals interactions. After oral administration, <b>8b</b> raised mouse blood levels of all three branched chain amino acids as a consequence of BCATm inhibition

Discovery, SAR, and X‑ray Binding Mode Study of BCATm Inhibitors from a Novel DNA-Encoded Library

As a potential target for obesity, human BCATm was screened against more than 14 billion DNA encoded compounds of distinct scaffolds followed by off-DNA synthesis and activity confirmation. As a consequence, several series of BCATm inhibitors were discovered. One representative compound (<i>R</i>)-3-((1-(5-bromothiophene-2-carbonyl)­pyrrolidin-3-yl)­oxy)-<i>N</i>-methyl-2′-(methylsulfonamido)-[1,1′-biphenyl]-4-carboxamide (<b>15e</b>) from a novel compound library synthesized via on-DNA Suzuki–Miyaura cross-coupling showed BCATm inhibitory activity with IC₅₀ = 2.0 μM. A protein crystal structure of <b>15e</b> revealed that it binds to BCATm within the catalytic site adjacent to the PLP cofactor. The identification of this novel inhibitor series plus the establishment of a BCATm protein structure provided a good starting point for future structure-based discovery of BCATm inhibitors