872017-40-8Relevant academic research and scientific papers
Identification of a dual δ or antagonist/μ or agonist as a potential therapeutic for diarrhea-predominant Irritable Bowel Syndrome (IBS-d)
Breslin, Henry J.,Diamond, Craig J.,Kavash, Robert W.,Cai, Chaozhong,Dyatkin, Alexey B.,Miskowski, Tamara A.,Zhang, Sui-Po,Wade, Paul R.,Hornby, Pamela J.,He, Wei
, p. 4869 - 4872 (2012)
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 = 1.3 nM; r Ki μ = 0.9 nM; h Ki μ = 1.7 nM), with less affinity for the κ OR (gp Ki 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 IC50 = 89 nM (HVD); μ EC50 = 1 nM (GPI); κ EC50 = 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.
