Discovery of Axelopran (TD-1211): A Peripherally Restricted μ-Opioid Receptor Antagonist

被引：9

作者：

Long, Daniel D. ^{[1
]}

Armstrong, Scott R. ^{[1
]}

Beattie, David T. ^{[1
]}

Campbell, Christina B. ^{[1
]}

Church, Timothy J. ^{[1
]}

Colson, Pierre-Jean ^{[1
]}

Dalziel, Sean M. ^{[1
]}

Jacobsen, John R. ^{[1
]}

Jiang, Lan ^{[1
]}

Obedencio, Glenmar P. ^{[1
]}

Rapta, Miroslav ^{[1
]}

Saito, Daisuke ^{[1
]}

Stergiades, Ioanna ^{[1
]}

Tsuruda, Pamela R. ^{[1
]}

Van Dyke, Priscilla M. ^{[1
]}

Vickery, Ross G. ^{[1
]}

机构：

[1] Theravance Biopharma US Inc, 901 Gateway Blvd, San Francisco, CA 94080 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 12期

关键词：

mu-Opioid receptor antagonists; multivalent approach; peripherally restricted; opioid-induced constipation; INDUCED CONSTIPATION; BRAIN; METHYLNALTREXONE; ALVIMOPAN;

D O I：

10.1021/acsmedchemlett.9b00406

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The effects of opioids in the central nervous system (CNS) provide significant benefit in the treatment of pain but can also lead to physical dependence and addiction, which has contributed to a growing opioid epidemic in the United States. Gastrointestinal dysfunction is an additional serious consequence of opioid use, and this can be treated with a localized drug distribution of a non-CNS penetrant, peripherally restricted opioid receptor antagonist. Herein, we describe the application of Theravance's multivalent approach to drug discovery coupled with a physicochemical property design strategy by which the N-substituted-endo-3-(8-aza-bicyclo[3.2.1]oct-3-yl)-phenyl carboxamide series of mu-opioid receptor antagonists was optimized to afford the orally absorbed, non-CNS penetrant, Phase 3 ready clinical compound axelopran (TD-1211) 19i as a potential treatment for opioid-induced constipation.

引用

页码：1641 / 1647

页数：13

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