Potent, Orally Bioavailable Delta Opioid Receptor Agonists for the Treatment of Pain: Discovery ofN,N-Diethyl-4-(5-hydroxyspiro[chromene-2,4′-piperidine]-4-yl)benzamide (ADL5859)

Selective 6 opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable 6 agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.