Novel mGlu5 negative allosteric modulators as first-in-class non-addictive analgesic therapeutics

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Project Summary An extensive literature provides compelling evidence that selective antagonists or negative allosteric modulators (NAMs) of the metabotropic glutamate (mGlu) receptor, mGlu5, have exciting potential as a novel approach for treatment of multiple pain conditions that could provide sustained antinociceptive activity without the serious adverse effects and abuse liability associated with opioids. While a number of mGlu5 NAMs have been advanced to clinical testing, the previous compounds all suffer from serious shortcomings, including poor pharmacokinetic properties and toxicity that have prevented their further development. Therefore, these prior compounds have not allowed for clinical studies to rigorously test this hypothesis in patients. We have developed a novel series of highly selective mGlu5 NAMs that are structurally unrelated to previous compounds, have excellent properties for further development, and avoid the formation of toxic metabolites that were associated with previous mGlu5 NAMs. Based on existing preclinical models, as well as clinical trial data showing efficacy of an mGlu5 NAM in migraine patients, we anticipate that our compounds will have broad-spectrum analgesic activity in patients with a variety of chronic pain conditions. It will be essential that new pain drugs do not suffer from abuse liability or severe toxicity that would prevent chronic administration, and these issues are addressed in the current research plan. We have completed the lead optimization and in vivo pharmacokinetic (PK) studies and identify multiple preclinical candidates. Preclinical proof of concept studies will now be conducted with our lead compound to test the hypothesis that mGlu5 NAMs will be efficacious in the treatment of pain without abuse liability. Additionally, we will perform positron emission tomography studies to determine in vivo receptor occupancy on the lead candidate. Efficacy data from these studies will be used to clearly establish a PK/PD/CNS receptor occupancy relationship and inform human dose projections and advance the program to the campaign 1 phase of the UH3 phase of this HEALS award. If UG3 milestones are met, a UH3 phase, in partnership with NIH contractors, will include all chemistry, manufacturing and control (CMC) and possibly safety pharmacology and toxicology studies required to prepare a preclinical candidate (PCC) for an investigation new drug (IND) application submission.