Abstract:
: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 μ-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.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Long DD,Armstrong SR,Beattie DT,Campbell CB,Church TJ,Colson PJ,Dalziel SM,Jacobsen JR,Jiang L,Obedencio GP,Rapta M,Saito D,Stergiades I,Tsuruda PR,Van Dyke PM,Vickery RGdoi
10.1021/acsmedchemlett.9b00406subject
Has Abstractpub_date
2019-11-26 00:00:00pages
1641-1647issue
12issn
1948-5875journal_volume
10pub_type
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