Parmodulins without Abuse Potential for the Treatment of Neuropathic Pain

Function Therapeutics, Inc., Milwaukee WI

Investigators

Abstract

PROJECT SUMMARY Neuropathic pain, a chronic condition from nerve damage frequently caused by physical injury, diabetes, or chemotherapy, is a debilitating situation that affects up to 10% of people worldwide. Current therapies are helpful but clearly inadequate; 17% of people in one survey described their neuropathic pain as “worse than death”. New classes of medicines for neuropathies are urgently needed, especially those lacking abuse potential and without onerous side effects. Evidence has accumulated pointing to inflammatory signaling driven by extracellular proteases as a driver of pain and neurodegenerative processes. The critical coagulation enzyme thrombin, and other proteases such as matrix metalloproteinases, have been connected to neuroinflammation and/or neurodegeneration in certain models. Direct inhibition of thrombin and other extracellular proteases is possible but frequently problematic, due to their pleiotropic effects on numerous targets. Alternatively, one can modulate these pathways by targeting certain membrane proteins, typically GPCRs or integrins, acting as their receptors. We have identified and characterized a new class of small molecules, called parmodulins, that allosterically modify the signaling of a receptor for thrombin, protease-activated receptor 1 (PAR1). In this manner, parmodulins can bias PAR1 signaling from a pro-inflammatory to an anti-inflammatory cyto- and barrier-protective phenotype, in a manner analogous to the action of the anti-inflammatory activated protein C (APC), which also acts at PAR1. This project will investigate the use of parmodulins for the treatment of neuropathic pain from physical injury, and will test in part the hypothesis that neuropathic pain is associated with permeability of the blood-spinal cord barrier. In Aims 1 and 2, a range of novel parmodulins will be synthesized and tested for PAR1 activity, selectivity, and maintenance of endothelial barriers, using assays developed in our labs. Drug-like properties (including solubility and stability) will be measured for active compounds, and optimal examples will undergo rodent pharmacokinetic studies to measure bioavailability and other parameters, to determine their potential for chronic oral dosing. Several representative parmodulins will progress to Aim 3, where they will be tested for analgesic effects in a rat spared nerve injury model. Sensitivity to pressure and heat will be measured using standard protocols, and potential behavioural impairments from novel compounds will be measured. Blood- spinal cord barrier integrity will be determined by dosing with Evans Blue and measuring extravasation to the lumbar spinal cord. The lack of abuse potential of the parmodulin class of anti-inflammatories will be confirmed with a self-administration study in rats. Promising results in these proof-of-concept studies will justify the preclinical development of parmodulins for the treatment of neuropathic pain from physical injury, and potentially other neurodegenerative disorders.