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

被引：49

作者：

Breslin, Henry J. ^{[1
]}

Diamond, Craig J. ^{[1
]}

Kavash, Robert W. ^{[1
]}

Cai, Chaozhong ^{[1
]}

Dyatkin, Alexey B. ^{[1
]}

Miskowski, Tamara A. ^{[1
]}

Zhang, Sui-Po ^{[1
]}

Wade, Paul R. ^{[1
]}

Hornby, Pamela J. ^{[1
]}

He, Wei ^{[1
]}

机构：

[1] Janssen Res & Dev LLC, Spring House, PA 19477 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 14期

关键词：

Mixed delta OR antagonist/mu OR agonist; Opioid receptor; Irritable Bowel Syndrome; IBS-d; OPIOID RECEPTOR AGONISTS; PHENYL IMIDAZOLES;

D O I：

10.1016/j.bmcl.2012.05.042

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：4869 / 4872

页数：4

共 14 条

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