GNE-131

Pain is a symptom of ninety percent of human diseases, and pain management is a very important medicinal problem. Various modulators of the pain response have been detected, and analgesic effects are obtained by increasing inhibition or decreasing excitation in the nervous system. Various known analgesic drugs are commonly used to relieve the pain; however, this problem is still not fully resolved by currently available treatments. Available analgesic drugs (non-steroidal anti-inflammatory drugs, opioids and analgesic adjuvants) are not too effective and are severely limited by adverse effects, for example, opioid addiction. Therefore, developing effective pain management is a difficult but necessary task. Thus, there is an urgent need for further development of the design and synthesis of new analgesic agents. The aim of this review is to present recent progress in search of new small molecule analgesics. The structures and effects of new perspective analgesic agents (anti-inflammatory agents, opioid analgesics, adjuvant agents for pain management, and natural compounds) are presented and discussed. The review covers the literature published in 2015-2020 years and includes 173 references.

The sodium channel Na_V1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of Na_V1.7, with high selectivity over the cardiac isoform Na_V1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective Na_V1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of Na_V1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.