Peptide-Derived Orally-Active Kappa-Opioid Receptor Agonists for Peripheral Pain

DESCRIPTION (provided by applicant): 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-NH2such 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 acti