Development of Angiotensin AT2 inhibitors for neuropathic pain relief

University Of Southern California, Los Angeles CA

Investigators

Abstract

Project Summary Neuropathic chronic pain affects ~20 million Americans and bears more than US$500 Billion burden on the US economy. Moreover, the widespread use of addictive opioid painkillers for chronic pain is the major root of the opioid abuse epidemic threatening the whole society. As only one in four patients with neuropathic pain experiences pain relief with the current treatment options, the discovery of new approaches to treating neuropathic pain is an unmet medical need with a major impact on society. Targeting pain in peripheral nerves is a key paradigm for effective and safe analgesia, which can naturally bypass the CNS-mediated side effects and addiction. One of the most promising and advanced peripheral targets, angiotensin AT2 receptor is involved in regulations of neuronal membrane excitability and neurite outgrowth of peripheral sensory neurons. Inhibition of AT2R in PNS has shown effect in preclinical models of neuropathic pain, as well as in phase II clinical trials, where the EMA401 drug candidate demonstrated analgesia in patients with post-herpetic neuralgia and diabetic neuropathy. However, EMA401, which had modest potency and suboptimal drug-like properties, was terminated in May 2019 due to off-target hepatotoxicity at high therapeutic doses. The lack of suitable candidates in the pipeline strongly differentiated from EMA401 calls for the development of new highly potent and safe AT2R antagonists for neuropathic pain. We have established a structure-based drug discovery platform and used it to identify and optimize a novel lead series of AT2R antagonists, highly efficient in two murine models on neuropathic pain. Our best lead series compound showed better potency and in vivo efficacy than EMA401, as well as better ADMET and PK profiles, in mouse, rat and dog with minimal liver accumulation. Here, we propose additional optimization of the lead analogs focusing on eliminating a platelet depletion side effect - the last remaining liability of our current candidate. Our preliminary results have identified a first backup compound that maintains high efficacy without significant platelet depletion, showing the feasibility of separating the therapeutic from the side effect. At the UG3 stage, we will employ medicinal chemistry optimization of the lead analogs, coupled with the previously established screening funnel and validated murine platelet counting assays to identify the best new candidate for preclinical development. At the UH3 stage, we will continue preclinical studies, IND submission, and Phase 1 clinical studies toward the characterization of this novel safe and effective neuropathic pain treatment.