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 δ and µ ORs (r K(i) δ=1.3 nM; r K(i) µ=0.9 nM; h K(i) µ=1.7 nM), with less affinity for the κ OR (gp K(i) κ=55 nM). The OR functional profile for 5l varied from the previously described dual δ/µ OR agonists 4, with 5l being a potent, mixed dual δ OR antagonist/µ OR agonist [δ IC(50)=89 nM (HVD); µ EC(50)=1 nM (GPI); κ EC(50)=1.6 µM (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.