Abstract
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 Ki δ=1.3nM; r Ki μ=0.9nM; h Ki μ=1.7nM), with less affinity for the κ OR (gp Ki κ=55nM). 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 IC50=89nM (HVD); μ EC50=1nM (GPI); κ EC50=1.6μM (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.
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