Discovery of novel tetrahydro-pyrazolo [4,3-c] pyridines for the treatment of neuropathic pain: Synthesis and neuropharmacology

•Synthesis of pharmacophoric hybrids of aryl semicarbazides into the tetrahydropyrido-pyrazoles pharmacophore.•Acute nociceptive assays performed.•Chronic constriction injury and partial sciatic nerve ligation models in animals were used.•Quantification of ED50 for most potential analogues determined.•Mechanistic studies for cannabinoid receptor, TNF-alpha, and oxidative stress evaluated.

We disclose the discovery of a novel series of tetrahydropyrido-pyrazoles that are potent inhibitors of tumour necrosis factor-alpha (TNF-α), nitric oxide and cannabinoid receptor subtype 1 (CB1). We report herein the synthesis and neuropharmacological screening results of the titled compounds in two acute pain and two neuropathic pain models in rodents. Particularly the analogue N-(4-bromophenyl)-3-tert-butyl-5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-carboxamide (8a) exhibited pronounced acute antinociceptive efficacy, also being effective in chronic constriction injury (ED50 = 23.8 mg/kg) and partial sciatic nerve injury (ED50 = 29.0 mg/kg) models with CB1 receptor activity (IC50 = 49.6 nM) and inhibitory effect on TNF-α (86.4% inhibition at 100 mg/kg). These results suggest the importance of the development of this lead as multi-targeted treatment strategy for neuropathic pain.

Graphical abstractWe disclose the discovery of a novel series of tetrahydropyrido-pyrazoles that are potent inhibitors of tumour necrosis factor-alpha (TNF-α), nitric oxide and cannabinoid receptor subtype 1 (CB1).Figure optionsDownload full-size imageDownload as PowerPoint slide