L-168049

L-168049 is a potent, selective, orally active and non-competitive glucagon receptor antagonist with IC₅₀s of 3.7 nM, 63 nM, and 60 nM for human, murine, and canine glucagon receptors, respectively^[1][2]. IC50 & Target: IC50: 3.7 nM (human glucagon receptor), 63 nM (murine glucagon receptor), and 60 nM (canine glucagon receptor)^[2] In Vitro: L-168049 (compound 49) inhibits glucagon (100 pM) stimulated cAMP synthesis in CHO cells expressing the human glucagon receptor (hGIAR) (IC₅₀ of 41 nM). L-168049 blocks cAMP formation stimulated by glucagon in murine liver membranes^[1].
L-168049 increases the apparent EC₅₀ for glucagon stimulation of adenylyl cyclase in Chinese hamster ovary cells expressing the human glucagon receptor and decreases the maximal glucagon stimulation observed, with a K_b of 25 nM^[2]. In Vivo: In the liver of L-G6pc ^/- mice, Pck1 mRNA expression is decreased by half 6 h after the administration of L-168049 (50 mg/kg body; p.o.), demonstrating the efficiency of the suppression of glucagon signaling. In agreement with the role of glucagon in the induction of extrahepatic gluconeogenesis, the administration of the L-168049 prevents the increase of the G6pc expression in both the kidneys and intestine of 6 h-fasted L-G6pc ^/- mice^[3].