Abstract Oral mu-opioid receptor (MOR) agonists with high receptor level activity remain the primary treatment for pain (about 702 million oral opioid pain prescriptions are dispensed per year in the US). However, these compounds are addictive and have dangerous levels of respiratory depression. MOR agonists that are classified as “weaker” like buprenorphine and tramadol reduce these serious adverse events (SAE), but they retain many liabilities that keep them from displacing more addictive and dangerous compounds like oxycodone. Up to 25% of patients receiving opioid prescriptions are at risk of addiction or an SAE that requires medical care. Stemming this tide requires a better partial MOR agonist. Using a novel MOR-ligand scaffold, Epiodyne has developed a promising series of potent orally bioavailable drug-like small molecules. From this series, our development candidate EPD2520 was selected; EPD2520 is a MOR partial agonist, that exhibits analgesic efficacy comparable to non-lethal doses of oxycodone, with little to no respiratory depression, and with apparently less abuse liability in rats than buprenorphine. In addition to a promising behavioral profile, EPD2520 also appears to be suitable for chronic administration. Safety issues were not detected in in-vitro screens including receptor selectivity, carcinogenicity, QT prolongation, metabolism ID and CYP inhibition assays. In this project we will 1) advance EPD2520 to IND enabling studies and file an IND. And 2) investigate novel ligand-receptor-physiology interactions to design 2nd generation compounds that build on the efficacy, drug like properties and reduced liabilities of EPD2520. We anticipate that EPD2520 will be a highly efficacious analgesic with reduced respiratory and addiction liabilities.