Adomeglivant (LY2409021)

Adomeglivant is an allosteric antagonist of the glucagon receptor.^1,2 It inhibits glucagon-induced increases in cAMP levels in HEK293 cells expressing the rat glucagon or GLP-1 receptors (IC₅₀s = 1.8 and 1.2 ?M, respectively) but has no effect on cAMP levels when used alone.² Adomeglivant also inhibits increases in cAMP levels induced by GLP-1 or exendin-4 (48-86) amide in HEK293 cells expressing the GLP-1 receptor (IC₅₀s = 7 and 12 ?M, respectively). It decreases glucose-stimulated insulin secretion when used at a concentration of 1 ?M in combination with the GLP-1 receptor antagonist exendin (9-39) in isolated human islets but not glucose-stimulated glucagon secretion when used alone or in combination with exendin (9-39) in isolated mouse islets.³

1.Li, Y., Ye, Z., Bellman, T.M., et al.Efficient synthesis of β-CF3/SCF3-substituted carbonyls via copper-catalyzed electrophilic ring-opening cross-coupling of cyclopropanolsOrg. Lett.17(9)2186-2189(2015) 2.Chepurny, O.G., Matsoukas, M.-T., Liapakis, G., et al.Non-conventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMPJ. Biol. Chem.2943514-3531(2019) 3.Zhu, L., Dattaroy, D., Pham, J., et al.Intraislet glucagon signaling is critical for maintaining glucose homeostasisJCI Insight4(10)e127994(2019)