Identification of a dual δ OR antagonist/μ OR agonist as a potential therapeutic for diarrhea-predominant Irritable Bowel Syndrome (IBS-d)

A small set of acyclic analogs 5 were prepared to explore their structure-activity relationships (SARs) relative to heterocyclic core, opioid receptor (OR) agonists 4. Compound 5l was found to have very favorable OR binding affinities at the delta and mu ORs (r K-i delta = 1.3 nM; r K-i mu = 0.9 nM; h K-i mu = 1.7 nM), with less affinity for the kappa OR (gp K-i kappa = 55 nM). The OR functional profile for 5l varied from the previously described dual delta/mu OR agonists 4, with 5l being a potent, mixed dual delta OR antagonist/mu OR agonist [delta IC50 = 89 nM (HVD); mu EC50 = 1 nM (GPI); kappa EC50 = 1.6 mu M (GPC)]. Compound 5l has progressed through a clinical Phase II Proof of Concept study on 800 patients suffering from diarrhea-predominant Irritable Bowel Syndrome (IBS-d). This Phase II study was recently completed successfully, with 5l demonstrating statistically significant efficacy over placebo. (C) 2012 Elsevier Ltd. All rights reserved.