Development of positive TMEM97 modulators for treating neuropathic pain

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Nearly a third of Americans suffer from chronic pain, but opioids, which are the most commonly used pain reliev- ers, are addictive, rapidly produce tolerance, impair motor performance, and are of limited efficacy for neuro- pathic pain. There is thus an urgent unmet need for the discovery and development of novel drugs that alleviate neuropathic pain through non-opioid and non-addicting mechanisms. We recently discovered several novel com- pounds that bind to the sigma-2 receptor, which we identified as transmembrane protein 97 (TMEM97), that relieve pain in an animal model of neuropathic pain with high and lasting efficacy and with no observable toler- ance when dosed repeatedly. These effects are absent in Tmem97 knockout (KO) mice, demonstrating the specificity of small molecule modulation of TMEM97 in vivo. These significant findings represent a breakthrough in the area of pain management because it opens the door to a completely new approach to treat neuropathic pain. The goal of the proposed optimization program is to identify at least one IND-enabled, positive TMEM97 modulator to treat neuropathic pain. We will achieve this goal in two distinct phases. In the UG3 Phase, we will prepare less lipophilic analogs of our current lead rac-FEM1689 to reduce safety liabilities, including hERG ac- tivity, while retaining efficacy, potency, TMEM97 affinity and specificity, and bioavailability. These optimization studies will be achieved in an iterative fashion by the synthesis and evaluation of analogs of rac-FEM1689 and involve determining: (1) TMEM97 affinities; (2) p-eIF2a inhibition in human Caco-2 cells to assess the putative role of blocking activation of the integrated stress response, which is known to be associated with neuropathic pain; (3) aqueous solubility (4) hERG channel activity; (5) in vitro DMPK; (6) in vivo PK; (7) efficacy in the rat Spared Nerve Injury model; and (8) efficacy in human dorsal root ganglion (DRG) neurons. These studies will result in the selection of a lead compound and one or more backup compounds for advancement to the next phase. In the UH3 Phase, we will test the lead and backup compounds in the human DRG electrophysiology assay to assess reversal of cytokine-induced hyperexcitability in human DRG nociceptors. We will conduct broad screens with the SafetyScreen87 CEREPS panel and use these and other PK data to determine a dose range where there is efficacy with minimal probability of off-target effects. Other IND-enabling studies will include screening for optimal salt form and characterization, preclinical toxicology, refinement of the synthetic route for GMP manufacturing, completion of the first pilot batch, as well as analytical method development and determination of impurity profile. The proposed studies are significant because they will validate TMEM97 as a new target for developing drugs that relieve neuropathic pain, and they will lead to the discovery of at least one positive TMEM97 modulator as a development candidate to treat neuropathic pain by a non-opioid pathway with low addiction potential.