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

详细信息    查看全文

• 作者：Perumal Yogeeswari ; Monika Sharma ; Ganesh Samala ; Matharasala Gangadhar ; Srirama Karthick ; Saketh Mallipeddi ; Arvind Semwal ; Dharmarajan Sriram
• 关键词：Antihyperalgesic ; Antiallodynic ; Tetrahydropyrazolo-pyridine ; Cannabinoid receptor ; Nitric oxide ; Antioxidant
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August, 2013
• 年：2013
• 卷：66
• 期：Complete
• 页码：211-220
• 全文大小：568 K

文摘

We disclose the discovery of a novel series of tetrahydropyrido-pyrazoles that are potent inhibitors of tumour necrosis factor-alpha (TNF-¦Á), 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 (dFont"">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-¦Á (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.