Author: Hanson, Julien ; Laufer, Stefan A ; Pillaiyar, Thanigaimalai ; Stäubert, Claudia ; Kronenberger, Thales ; Poso, Antti ; Liebing, Aenne-Dorothea ; Wozniak, Monika ; Abboud, Dayana ; Rasch, Alexander

The orphan G protein-coupled receptor GPR27 appears to play a role in insulin production, secretion, lipid metabolism, neuronal plasticity, and l-lactate homeostasis. However, investigations on the function of GPR27 are impaired by the lack of potent and efficacious agonists. We describe herein the development of di- and trisubstituted benzamide derivatives 4a-e, 7a-z, and 7aa-ai, which display GPR27-specific activity in a β-arrestin 2 recruitment-based assay. Highlighted compounds are PT-91 (7p: pEC₅₀ 6.15; E_max 100%) and 7ab (pEC₅₀ 6.56; E_max 99%). A putative binding mode was revealed by the docking studies of 7p and 7ab with a GPR27 homology model. The novel active compounds exhibited no GPR27-mediated activation of G proteins, indicating that the receptor may possess an atypical profile. Compound 7p displays high metabolic stability and brain exposure in mice. Thus, 7p represents a novel tool to investigate the elusive pharmacology of GPR27 and assess its potential as a drug target.

Journal of Medicinal Chemistry

Development of Ligands for the Super Conserved Orphan G protein-coupled Receptor GPR27 with improved efficacy and potency

Author: Staeubert, Claudia ; Kronenberger, Thales ; Poso, Antti ; Pillaiyar, Thanigaimalai ; Liebing, Aenne-Dorothea ; Laufer, Stefan A. ; Hanson, Julien ; Rasch, Alexander ; Wozniak, Monika ; Abboud, Dayana

The orphan G protein-coupled receptor GPR27 appears to play a role in insulin production, secretion, lipid metabolism, neuronal plasticity, and L-lactate homeostasis.However, investigations on the function of GPR27 are impaired by the lack of potent and efficacious agonists.We describe herein the development of di- and trisubstituted benzamide derivatives 4a-e, 7a-z, and 7aa-ai, which display GPR27-specific activity in a β-arrestin 2 recruitment-based assay.Highlighted compounds are PT-91 (7p: pEC50 6.15; Emax 100%) and 7ab (pEC50 6.56; Emax 99%).A putative binding mode was revealed by the docking studies of 7p and 7ab with a GPR27 homol. model.The novel active compounds exhibited no GPR27-mediated activation of G proteins, indicating that the receptor may possess an atypical profile.Compound 7p displays high metabolic stability and brain exposure in mice.Thus, 7p represents a novel tool to investigate the elusive pharmacol. of GPR27 and assess its potential as a drug target.Structure-activity relationships of the first series on GPR27 V2pEC50 values were measured in a β-arrestin 2 recruitment-based Firefly Luciferase complementation assay.Data points represent the mean ± SEM of three replicates.The activity of all compounds was verified in at least 2 independent experimentsThe pEC50 of the reference compound I is given in brackets for comparison with each tested compoundEmax is expressed as the percentage of the maximal activity of the lead compound I. n.d. = not determined

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus	Preclinical	Belgium	University of Liege	07 Dec 2023

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