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GSK2982772

Product NameGSK2982772
CAS1622848-92-3
MFC20H19N5O3
MW377.4
EINECS
MOL File1622848-92-3.mol

Chemical Properties

Density	1.40±0.1 g/cm3(Predicted)
storage temp.	-20°C
solubility	Soluble in DMSO (>25 mg/ml)
form	solid
pka	8.80±0.40(Predicted)
color	Off-white
Stability	Stable for 2 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.
InChIKey	LYPAFUINURXJSG-AWEZNQCLSA-N
SMILES	N1C(C(N[C@@H]2C(=O)N(C)C3=CC=CC=C3OC2)=O)=NC(CC2=CC=CC=C2)=N1

Usage And Synthesis

Description

(S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide, also known as GSK2982772, is a first-in-class receptor interacting protein 1(RIP1)-kinase specific clinical candidate for the treatment of inflammatory disease. It is an inhibitor of RIP1 that regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. It has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants.

Uses

GSK2982772 is a potent, orally active and ATP competitive RIP1 kinase inhibitor with IC50 values of 16 nM and 20 nM for human and monkey RIP1, respectively[1].

in vivo

GSK2982772 is dosed orally 15 min prior to TNF and shows 68, 80, and 87% protection from temperature loss over 6 h, at doses of 3, 10, and 50 mg/kg, respectively. In the corresponding TNF/zVAD model, GSK2982772 shows 13, 63, and 93% protection from temperature loss over 3 h. GSK2982772 displays a good free fraction in blood in rats (4.2%), dogs (11%), cynomolgus monkeys (11%), and humans (7.4%). The inhibitor has a good pharmacokinetic profile across both rats and monkeys. GSK2982772 distributes into a range of tissues including the colon, liver, kidney, and heart at concentrations comparable to those of blood. However, GSK2982772 has low brain penetration in rat (4%) despite possessing good cell permeability (21×10^-6 cm/s)^[1].

References

Harris, P. A., et al. "Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases." Journal of Medicinal Chemistry 60.4(2017):1247-1261.
Jeong, Jae Uk, et al. "Synthesis of ( S )-3-amino-benzo[ b ][1,4]oxazepin-4-one via Mitsunobu and S N Ar reaction for a first-in-class RIP1 kinase inhibitor GSK2982772 in clinical trials." Tetrahedron Letters 58.23(2017):2306-2308.

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