Progress in the development of kynurenine and quinoline-3-carboxamide-derived drugs

The diverse neuro- and immunomodulatory effects of kynurenine pathway (KP) enzymes and metabolites exert offer possibilities for intervention in diseases such as autoimmunity, neurodegeneration, and neoplastic processes.

This review focuses on data obtained from the preclinical and clinical use of a KP metabolite analog and structurally related compounds. 4-Cl-KYN has completed clinical trials in depression without success. However, the good safety data give hope for further trials in suicide prevention, neuropathic pain, and dyskinesia. Quinoline-3-carboxamide derivatives laquinimod, paquinimod, and tasquinimod show structural similarities to kynurenines. Laquinimod and paquinimod show promising results in the treatment of autoimmune diseases, tasquinimod is considered primarily as an anti-cancer drug. Data available until 31 May 2020 at Clinicaltrials.gov and PubMed have been reviewed.

The failure of 4-Cl-KYN for use as an anti-depressant may be related to inadequate concentration, or that the ketamine-like rapid anti-depressant effect is not produced via NMDAR modulation. Further clarification may emerge from studies involving higher drug concentration, and/or from identification of ketamine targets. Clinical application trials in very diverse indications of structurally related quinoline-3-carboxamides and the wide range of their mode of action warrant further studies permitting direct comparison of effects and better target identification.