Discovery of 1‑(Hetero)aryl-β-carboline Derivatives as IDO1/TDO Dual Inhibitors with Antidepressant Activity

Depression is the leading cause of global burden of disease
and
disability. Abnormalities in the kynurenine pathway of tryptophan
degradation have been closely linked to the pathogenesis of depression.
An integrative bioinformatics analysis demonstrated that indoleamine
2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are
potential targets for the development of antidepressants. A series
of 1-(hetero)­aryl-β-carboline derivatives were designed, synthesized,
and evaluated as novel IDO1/TDO dual inhibitors. Among them, compound 28 displayed potent inhibition of both IDO1 (IC50 = 3.53 μM) and TDO (IC50 = 1.15 μM) and had
an acceptable safety profile and pharmacokinetic properties. Compound 28 also rescued lipopolysaccharide-induced depressive-like
behavior in mice. Further studies revealed that 28 likely
had unique antidepressant mechanisms involving suppressing microglial
activation, lowering IDO1 expression, and reducing proinflammatory
cytokine and kynurenine levels in the mouse brain. Overall, this work
provides practical guidance for the development of IDO1/TDO dual inhibitors
to treat inflammation-induced depression.