Glucagon receptor antagonists (GRA) are novel molecules in development for the treatment of type 1 and type 2 (T2DM) diabetes. LGD-6972 recently demonstrated robust efficacy in a 12-week, Phase 2 study in T2DM, reducing HbA1c by 1.2% from baseline, with a safety profile more favorable than other GRAs at this stage of development. LGD-6972 is structurally distinct from other small molecule GRAs, containing a sulphonic acid tail (SAT) rather than a carboxylic acid tail (CAT), potentially explaining this finding. We performed computational modeling of LGD-6972 bound to the glucagon receptor (GCGR) and compared it to x-ray crystallography data with receptor bound MK-0893. The SAT of LGD-6972 creates a larger pocket between helix 6 and 7 in the GCGR transmembrane domain, and alters the orientation of helix 8. Activity of LGD-6972, MK-0893 and other SAT and CAT GRAs were examined in cellular models of glucagon-stimulated cAMP accumulation, β-arrestin recruitment, and receptor internalization. All tested GRAs were full (>95%) antagonists of cAMP accumulation. CAT GRAs were full antagonists of β-arrestin (≥96%) and receptor internalization (≥94%). In contrast, SAT GRAs had reduced antagonism of β-arrestin (58-87%) and receptor internalization (6-52%). The relative potency was also altered with greater potency for CAT GRAs on β-arrestin vs. cAMP, whereas the opposite was true for SAT GRAs. Furthermore, a LGD-6972 analog with a CAT and a MK-0893 analog with a SAT displayed CAT- and SAT-like activity, respectively, indicating a clear structure-activity relationship exists, with LGD-6972 displaying receptor-biased signaling. To further investigate the potential differences among compounds, primary human hepatocytes were treated with glucagon or glucagon with MK-0893 or LGD-6972 and gene expression was analyzed by microarray. Broad differences between glucagon and the GRAs were observed and future studies will investigate the effects of SAT and CAT compounds.


E.G. Vajda: Employee; Self; Ligand Pharmaceuticals, Inc. L. Zhi: Employee; Self; Ligand Pharmaceuticals, Inc. K. Marschke: Employee; Self; Ligand Pharmaceuticals, Inc..

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