Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1
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Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1. / Rexen Ulven, Elisabeth; Trauelsen, Mette; Brvar, Matjaz; Lückmann, Michael; Bielefeldt, Line Ø; Jensen, Lisa K I; Schwartz, Thue W; Frimurer, Thomas M.
I: Scientific Reports, Bind 8, Nr. 1, 10010, 2018, s. 1-18.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Structure-Activity Investigations and Optimisations of Non-metabolite Agonists for the Succinate Receptor 1
AU - Rexen Ulven, Elisabeth
AU - Trauelsen, Mette
AU - Brvar, Matjaz
AU - Lückmann, Michael
AU - Bielefeldt, Line Ø
AU - Jensen, Lisa K I
AU - Schwartz, Thue W
AU - Frimurer, Thomas M.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - 10.1038/s41598-018-28263-7
DO - 10.1038/s41598-018-28263-7
M3 - Journal article
C2 - 29968758
VL - 8
SP - 1
EP - 18
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 10010
ER -
ID: 211856788