MK 0893

MK 0893 (CAS No. 870823-12-4) is a competitive, reversible glucagon receptor (GCGR) antagonist [1][3]. Its core biological function is to bind an extra-helical allosteric site (non-orthosteric site) between TM6 and TM7 of GCGR, forming polar interactions with residues such as Arg346, Lys349, Ser350, and Asn404, thereby restricting the outward helical movement of TM6 and inhibiting receptor activation and G protein coupling [3][4]. It also shows some inhibitory activity against GIPR (IC₅₀ 1020 nM) and PAC1 (IC₅₀ 9200 nM) among class B GPCRs, with no significant inhibitory effect on GLP-1R or VPAC1/2 [1][3]. IC₅₀ data show: human GCGR binding IC₅₀ 6.6±3.5 nM and functional cAMP IC₅₀ 15.7±5.4 nM; rhesus monkey GCGR IC₅₀ 55.5 nM; mouse 122 nM; rat 727±350 nM; CYP2C8 inhibition IC₅₀ 2.7±0.2 μM and CYP2C9 14±1.8 μM [1][3][4]. Animal experiments are used for model treatment. Common models include the hGCGR mouse acute glucagon challenge model, the hGCGR ob/ob mouse obesity-diabetes model, the high-fat diet–induced hGCGR mouse chronic diabetes model, and the rhesus monkey glucagon challenge model [1][2][3].

Common working concentrations: in cell culture, CHO-hGCGR cells are used for receptor binding and functional assays (nM-range concentrations) [1][4]; in animal studies, mice oral 3-30 mpk, rats oral 3-10 mg/kg/d, and rhesus monkeys intragastric gavage 0.3-3 mpk [1][3]; clinically, type 2 diabetes patients received a single dose of 200-1000 mg and a 12-week maintenance dose of 60-80 mg qd [1][5].

Effective therapeutic concentrations: in animal studies, 3 mpk reduced blood glucose AUC by 32% in hGCGR ob/ob mice and 10 mpk reduced it by 39%; in high-fat diet mice, 3-10 mpk/d within 10 days reduced blood glucose by 89%-94%; in rhesus monkeys, 1-3 mpk reduced blood glucose by 55%-59% [1][3].

Clinically, 60-80 mg qd reduced fasting blood glucose by 53-63 mg/dL and glycated hemoglobin (HbA₁c) by 1.1%-1.5%; a single 200 mg dose blocked 59% of glucagon-induced blood glucose elevation [1][5]. In a 5-week repeated-dose safety study in rats, tolerability was good at daily doses ≤100 mg/kg [1].

References:

[1] Xiong Y, Guo J, Candelore M R, et al. Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3(3,5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes[J]. Journal of Medicinal Chemistry, 2012, 55(14): 6137-6148.

[2] Lin S, Zhang F, Jiang G, et al. A novel series of indazole-/indole-based glucagon receptor antagonists[J]. Bioorganic & Medicinal Chemistry Letters, 2015, 25(18): 4143-4147.

[3] Jazayeri A, Doré A S, Lamb D, et al. Extra-helical binding site of a glucagon receptor antagonist[J]. Nature, 2016, 533(7604): 274-277.

[4] Wang M, Fu X, Du L, et al. The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures[J]. International Journal of Molecular Sciences, 2024, 25(15): 8389.

[5] Chepurny O G, Matsoukas X M T, Liapakis G, et al. Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP[J]. Journal of Biological Chemistry, 2019, 294(10): 3514-3531.