Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1

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Elisabeth Rexen Ulven, Mette Trauelsen, Matjaz Brvar, Michael Lückmann, Line Ø Bielefeldt, Lisa K I Jensen, Thue W Schwartz, Thomas M. Frimurer

The succinate receptor 1 (SUCNR1) is a receptor for the metabolite succinate, which functions as a metabolic stress signal in the liver, kidney, adipose tissue and the retina. However, potent non-metabolite tool compounds are needed to reveal the physiological role and pharmacological potential of SUCNR1. Recently, we published the discovery of a computationally receptor-structure derived non-metabolite SUCNR1 agonist series with high target selectivity. We here report our structure-activity exploration and optimisation that has resulted in the development of agonists with nanomolar potency and excellent solubility and stability properties in a number of in vitro assays. Ligand-guided receptor models with high discriminative power between binding of active and inactive compounds were developed for design of novel chemotypes.

Original languageEnglish
Article number10010
JournalScientific Reports
Volume8
Issue number1
Pages (from-to)1-18
ISSN2045-2322
DOIs
Publication statusPublished - 2018

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