GNF4877| CAS 2041073-22-5|DC Chemicals

Cas No.:	2041073-22-5
Chemical Name:	CID 139600315
Synonyms:	GNF4877;(R)-1-(3-(3-Amino-6-(2-fluoro-5-isopropoxyphenyl)pyrazine-2-carboxamido)pyridin-4-yl)piperidine-3-carboxylic acid;GTPL10688;ZB1618;(3R)-1-[3-[[3-amino-6-(2-fluoro-5-propan-2-yloxyphenyl)pyrazine-2-carbonyl]amino]pyridin-4-yl]piperidine-3-carboxylic acid;CID 139600315;GNF 4877
SMILES:	FC1C=CC(=CC=1C1=CN=C(C(C(NC2C=NC=CC=2N2CCC[C@@H](C(=O)O)C2)=O)=N1)N)OC(C)C
Formula:	C₂₅H₂₇FN₆O₄
M.Wt:	494.518088579178
Purity:	>98%
Sotrage:	2 years -20°C Powder, 2 weeks 4°C in DMSO, 6 months -80°C in DMSO
Publication:	[1]. Shen W, et al. Inhibition of DYRK1A and GSK3β induces human β-cell proliferation. Nat Commun. 2015 Oct 26;6:8372.

Description:	GNF4877 is a potent DYRK1A and GSK3β inhibitor with IC50s of 6 nM and 16 nM, respectively, which leads to blockade of nuclear factor of activated T-cells (NFATc) nuclear export and increased β-cell proliferation (EC50 of 0.66 μM for mouse β (R7T1) cells)[1].
Target:	GSK3β:16 nM (IC50) DYRK1A:6 nM (IC50)
In Vivo:	GNF4877 (50 mg/kg; oral gavage; twice a day; for 15 days; double transgenic RIP-DTA male mice) treatment induces β-cell proliferation, increases β-cell mass and insulin content, and improves glycaemic control[1]. Animal Model: Double transgenic RIP-DTA male mice (Tg (Ins 2-rtTA) 2 Efr Tg (teto-DTA) 1 Gfi/J) with Doxycycline (28.8±2.4 g; 82±2 days)[1] Dosage: 50 mg/kg Administration: Oral gavage; twice a day; for 15 days Result: Induced β-cell proliferation, increased β-cell mass and insulin content, and improved glycaemic control.
In Vitro:	High glucose concentrations and glucokinase activators (GKAs) increase Ca2+ signalling in β-cells, and increase intracellular Ca2+ leads to activation of calcineurin and nuclear translocation of NFATc proteins. Indeed, concentrations of GNF4877 ((0.1 μM, 0.3 μM) well below the EC50 for β-cell proliferation are able to induce proliferation in the presence of high glucose or pharmacological activators of glucokinase. Finally, increasing intracellular Ca2+ with glibenclamide (a sulfonylurea receptor 1 inhibitor) or Bay K8644 (an L-type Ca2+ channel activator) show additive activity with GNF4877[1].
References:	[1]. Shen W, et al. Inhibition of DYRK1A and GSK3β induces human β-cell proliferation. Nat Commun. 2015 Oct 26;6:8372.

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CID 139600315(GNF-4877)