Further SAR of GIRK1/2 Activators: In Vitro Biological Characterization and Evaluation of Effects on Neuropathic and Inflammatory Pain in Rodents

The work presented herein outlines the ongoing structure-activity relationship (SAR) studies centered around a potent, efficacious, and selective activator of the GIRK1/2 channel. Optimization studies centered around the pyrazole privileged scaffold, the N-1-position of the pyrazole and the right-hand ether. The work confirmed the necessity of the pyrazole, and we have identified a more potent GIRK1/2 activator with ~12-fold selectivity against GIRK1/4. We also report the metabolite ID study which shows the instability of the amide bond as the major site of metabolism (non-NADPH mediated). This work discovered another highly potent and selective GIRK1/2 activator. As preclinical proof of concept studies in rodents, the lead 3 has demonstrated that direct activation of GIRK1/2 channels can produce potent analgesic effects on neuropathic pain model in mice induced by spared nerve injury. In addition, 3 was active in an inflammatory pain model of osteoarthritis (OA) induced by a single intra-articular (IA) injection of monosodium-iodoacetate (MIA) in the knee of the rat. Our studies shed light into a role of direct activation of GIRK1/2 channels in modulation of chronic pain.