Discovery of TD-8954, a clinical stage 5-HT 4 receptor agonist with gastrointestinal prokinetic properties

…, DD Long, DG Marquess, JP Shaw, RG Vickery

Index: McKinnell, R. Murray; Armstrong, Scott R.; Beattie, David T.; Fatheree, Paul R.; Long, Daniel D.; Marquess, Daniel G.; Shaw, Jeng-Pyng; Vickery, Ross G. Bioorganic and Medicinal Chemistry Letters, 2013 , vol. 23, # 14 p. 4210 - 4215

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Citation Number: 6

Abstract

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 ...