X‑ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease

Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase
(hTDO) have been closely linked to the pathogenesis of Parkinson’s
disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors
to evaluate their potential efficacy against PD is still lacking.
Here, we report biochemical, biophysical, and computational analyses
revealing that 1H-indazole-4-amines inhibit both
hIDO1 and hTDO by a mechanism involving direct coordination with the
heme ferrous and ferric states. Crystal structure-guided optimization
led to 23, which manifested IC50 values of
0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good
pharmacokinetic properties and brain penetration in mice. 23 showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced
mouse motor coordination deficits, comparable to Madopar, an anti-PD
medicine. Further studies revealed that different from Madopar, 23 likely has specific anti-PD mechanisms involving lowering
IDO1 expression, alleviating dopaminergic neurodegeneration, reducing
inflammatory cytokines and quinolinic acid in mouse brain, and increasing
kynurenic acid in mouse blood.