Development of Tranilast derivatives as a potential treatment of chronic pain

Chronic pain is one of the greatest challenges of modern medicine, as it impacts 1.5 billion people worldwide and the treatments used are mostly opioids, that lead to dependence and habituation issues. Tetrahydrobiopterin (BH₄)is a cofactor for several neurotransmitters involved in nociceptive sensations but is also vital at low levels. Sepiapterin reductase (SPR)is the main enzyme that allows BH₄ production via two different pathways. If inhibited, other enzymes will still allow for diminished production of BH₄ and pain will decrease. Therefore, several inhibitors of BH₄ have been tested to treat neuropathic pain in the last years such as N-acetylserotonin, SPRi3 and tranilast. In this project, derivatives of tranilast have been engineered to increase binding to hSPR and thus competitive inhibition. Through in silico testing by docking in ICM Molsoft, seven derivatives were selected for their binding potency similar to tranilast and higher than sepiapterin. These compounds have higher potential of inhibition of hSPR at low dosage and thus, could constitute viable drugs. Four derivatives of tranilast were synthesised by adaptation of chemical synthesis protocols existing for similar products. The compounds were tested in a biological assay comparing their affinity to hSPR with sepiapterin. Even with better in silico inhibition of SPR, the drugs did not prove more efficient than tranilast in vitro, especially at low dosage. The dose-response curves show the superiority of SPRi3.However, one compound–2-[(2E,4E)-5-(3,4-dimethoxyphenyl)penta-2,4-dienamido)benzoic acid–did show a similar potency to tranilast and could be further investigated in a cellular assay.