Discovery of TD-8954, a clinical stage 5-HT4 receptor agonist with gastrointestinal prokinetic properties

The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that o...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-07, Vol.23 (14), p.4210-4215
Main Authors: McKinnell, R. Murray, Armstrong, Scott R., Beattie, David T., Fatheree, Paul R., Long, Daniel D., Marquess, Daniel G., Shaw, Jeng-Pyng, Vickery, Ross G.
Format: Article
Language:English
Subjects:
5-HT4
agonists
Aromatics
benzimidazole
binding capacity
chemistry
gastrointestinal system
Multivalent approach
Prokinetic
serotonin
TD-8954
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Summary:The discovery of a series of 5-HT4 receptor agonists based on a novel 2-alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.05.018