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Small molecule glucagonR antagonist

Category
ID
Amount per vial
Glucagon
NNC0025-0926
20 mg

Glucagon is a 29 amino acid peptide hormone liberated in the alpha cells of the islets of Langerhans. Glucagon has in general been viewed as the counter regulatory hormone to insulin in peripheral tissues, predominantly to the liver. An important contributor to the development of hyperglycemia in type 2 diabetes is inappropriately high glucose production from the liver. The primary physiological effect of glucagon is to stimulate hepatic glucose production by increasing both gluconeogenesis and glycogenolysis. 

NNC0025-0926 was tdeveloped as an oral bioavailable small molecule capable of antagonizing the Glucagon signaling and thereby shut down the contribution from Glucagon to hyperglycemia in T2DM. 

CompoundNNC0025-0926
MW (Da)582.49
Sum formulaC30H29Cl2N3O5


Proton-NMR (DMSO-d6): d 1.50-1.80 (4H, m), 2.08-2.38 (4H, m), 3.36-3.65 (2H, m), 4.14-4.24 (1H, m), 4.96 (2H, m), 6.17 (1H, t), 7.14 (1H, t), 7.18 (2H, d), 7.35 (2H, d), 7.42 (2H, d), 7.63 (2H,d), 7.78 (2H, d), 8.48 (1H, t), 8.55 (1H, s).

Analytical chiral HPLC: Chiralcel OF 250x4.6 mm. Isocratic eluent; isopropanol:n-heptane:TFA: 80:20:0.1, Rt = 67.3 min. Purity > 99.5 % ee

The structure of NNC0025-0926
2D sketch of NNC0025-0926. (R)-3-{4-[1-(4-Cyclohex-1-enylphenyl)-3-(3,5-dichlorophenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid.

See the Kodra et al., 2008 reference listed in the reference section for further details.
AssayNNC0025-0926
Rat GlucR binding affinity (IC50, nM)43
Rat GIPR binding affinity (IC50, nM)501
Human GlucR binding affinity (IC50, nM)3.9
Human GIPR binding affinity (IC50, nM)359
GIPR: GIP receptor; GlucR: glucagon receptor

To examine the effects in vivo, NNC0025-0926 was tested in a glucagon-challenged rat model. The compound dose-dependently inhibited the glucagon-stimulated rise in blood glucose (see figure 3 in the Kodra et al. 2008 reference listed in the reference section). The minimum effective i.v. dose for NNC0025-0926 was 3 mg/kg.

ParameterNNC0025-0926
SpeciesRat
Oral bioavailability (%)32
Half-life after i.v. dose (min)53
CL (ml/min/kg) i.v. 26
Vz (l/kg) i.v. 0.91
CL: clearance; Vz: volume of distribution.

No reference compound available

Please note that the vial contains app. 20 mg and you need to check the exact amount in each vial. Formulation guide for a 3 mg/mL oral solution of NNC0025-0926: Hydroxypropyl-β-cyclodextrin (HBCD) stock solution: HBCD is dissolved in MilliQ water using magnet stirring to form a 20% w/w HBCD stock solution. NNC0025-0926 suspension: NNC0025-0926 is suspended in PEG 400 at a concentration of 15 mg/ml. Formulation:20% v/v NNC0025-0926 suspension is mixed with 50% v/v HBCD stock solution to form a suspension. 5% v/v 1.0 M NaOH is added to the NNC0025-0926 suspension to obtain a transparent solution (sonication may be used to wet NNC0025-0926). 20% 0.1 M phosphate buffer pH 7.2 is added. pH is of the solution is adjusted to 7.2 with 1 M NaOH or 1 M HCl (less than 5% v/v used).0.1 M Phosphate buffer pH 7.2 is added to obtain the final volume of formulation and a transparent solution is obtained. Formulation can be stored for 1 week at 5C without risk of precipitation and/or degradation of NNC0025-0926 in solution.
PEG: polyethylene glycol

Kodra JT et al.
Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insulinotropic polypeptide receptor
J. Med. Chem., 2008, 51, 5387–5396