Treatment of peripheral pain of various origins remains a major unmet medical need, affecting tens to hundreds of millions of people nationwide at some time during their lives. Kappa-opioid agonists have been shown in peripheral pain models to be particularly efficacious but suffer from centrally mediated effects that have limited their development. Perhaps the most promising kappa-agonists under development are derivatives of the tetrapeptide D-Phe-D-Phe-D-Nle-D-Arg-NH2 such as CR665, which exhibits high (but not absolute) peripheral to central (CNS) selectivity when administered IV. Clinical studies have shown significant benefit in patients with visceral and neuropathic pain;however, the compound is not active when administered orally which significantly limits its potential use as an analgesic for peripheral pain. As proof of concept, application of the Halimed Pharmaceuticals non- natural amino acid technology to CR665 produced derivatives that exhibit oral activity in the rodent acetic acid-induced writhing assay fo peripheral pain. We therefore hypothesize that application of the Halimed peptide modification technology to CR665 will result in an orally available peripheral kappa opioid receptor agonist that can be developed as a pharmaceutical entity. To evaluate this hypothesis, we will complete three Specific Aims.
Specific Aim 1 is identification of potential lead candidates. Three residues of CR665 will be modified in turn using the Halimed matrix approach to lead generation: first, the D-Arg(4) side-chain, second, the n-leu(3) side chain, third, the -(C=O)NH2 C-terminus. Each compound will be evaluated in the writhing model. After each screen, the best residue(s) identified can then be incorporated into compounds used for the subsequent screens. This approach effectively evaluates a structural space of 2100 derivatives of the lead peptide, maximizing the chance of finding exciting new chemical entity "hits" as kappa opioid receptor agonists.
Specific Aim 2 is determination of "leads" from "hits". At least two compounds emerging from Specific Aim 1 will be evaluated for characteristics to further define them as appropriate leads, which will include determination of EC50s, the peripheral to CNS potency ratios, and selectivity for the kappa- over the mu- and delta-opioid receptors. Minimal benchmark values for each evaluation have been defined.
Specific Aim 3 is evaluation of other potential opioid side effects, including dysphoria, sedation, respiratory depression, addiction/dependence and diuresis. Toxicology screening will be initiated by determining the maximal tolerated dose for each potential lead and evaluating the potential for tolerance development. Completion of these Specific Aims will identify well-characterized, vetted leads to justify entering formal preclinical development in Phase II of this project. This Phase I effort wil be performed at Halimed Pharmaceuticals and in collaboration with the PI's long-term collaborator, Dr. Craig Beeson, at the Medical University of South Carolina.

Public Health Relevance

Peripheral pain management remains a major unmet clinical need. This investigation will select preclinical leads from engineered derivatives of a peripherall specific, orally administered, kappa-opioid agonist that has analgesic activity, and perform studies justifying advancement of the leads into formal preclinical development as novel analgesics

National Institute of Health (NIH)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1)
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Rapaka, Rao
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Halimed Pharmaceuticals, Inc.
Mount Pleasant
United States
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