کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1369657 981784 2012 4 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Identification of a dual δ OR antagonist/μ OR agonist as a potential therapeutic for diarrhea-predominant Irritable Bowel Syndrome (IBS-d)
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Identification of a dual δ OR antagonist/μ OR agonist as a potential therapeutic for diarrhea-predominant Irritable Bowel Syndrome (IBS-d)
چکیده انگلیسی

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.

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ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry Letters - Volume 22, Issue 14, 15 July 2012, Pages 4869–4872
نویسندگان
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