Development of a Series of Aryl Pyrimidine Kynurenine Monooxygenase Inhibitors as Potential Therapeutic Agents for the Treatment of Huntington’s Disease

Abstract

We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.

The novel KMO inhibitor CHDI-340246 leads to a restoration of electrophysiological alterations in mouse models of Huntington's disease

“…Selectivity of CHDI-340246 against KAT isoforms, kynureninase and IDO have been previously reported (referred to as compound 75 in (Toledo-Sherman et al, 2015;Winkler et al, 2013). In the present study, additional radioligand displacement assays with 10 µM CHDI-340246 were conducted against a diverse panel of CNS and other peripheral targets was performed to assess off-target liability (Cerep, France).…”

“…Its properties have been described previously, as compound 75 (Toledo-Sherman et al, 2015). In biochemical assays against KMO using mitochondrial fractions isolated from rodent liver tissue, CHDI-340246 has an IC 50 of 0.5 nM.…”

“…In biochemical assays against KMO using mitochondrial fractions isolated from rodent liver tissue, CHDI-340246 has an IC 50 of 0.5 nM. In various cellular assays measuring endogenous KMO activity, including primary rat microglia and human peripheral blood cells (PBMCs), and in CHO cells overexpressing mouse, human or rat KMO, CHDI-340246 has a potency of 20-80 nM, depending on the assay format [ Figure 1 and (Toledo-Sherman et al, 2015)]. CHDI-340246 does not affect the activity of other enzymes in the KP, including IDO, KATs or kynureninase.…”

“…Concentrations of CHDI-340246 in mouse plasma, brain, kidney, liver, and dose solutions were determined using an LC-MS/MS assay as described previously (Toledo-Sherman et al, 2015). The lower limits of quantification (LLOQ) for this assay were 3.44 nM (plasma, kidney and liver) and 6.88 nM (brain).…”

“…Secondly, that the elevation of Kyn and KynA, on their own, would confer some benefit in HD models due to their neuroactive properties. We therefore developed an orally-bioavailable, potent and selective KMO inhibitor, CHDI-340246, to rigorously evaluate the involvement of KMO in disease progression (Toledo-Sherman et al, 2015;Winkler et al, 2013). We show a dose-dependent modulation of the KP metabolites in blood and in multiple tissues, including brain, after oral administration and provide a detailed quantitative pharmacokinetic-pharmacodynamic characterization of drug activity.…”