GSK2982772

• CAT Number: I007102
• CAS Number: 1622848-92-3
• Molecular Formula: C20H19N5O3
• Molecular Weight: 377.404
• Purity: ≥95%
• Synonyms: GSK2982772; GSK-2982772; GSK 2982772.;(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
• Target: RIP1 inhibitor
• Solubility: Soluble in DMSO
• Storage: 0 - 4°C for short term or -20 °C for long term
• Related CAS: 1987858-31-0(hydrate)
• InChI: InChI=1S/C20H19N5O3/c1-25-15-9-5-6-10-16(15)28-12-14(20(25)27)21-19(26)18-22-17(23-24-18)11-13-7-3-2-4-8-13/h2-10,14H,11-12H2,1H3,(H,21,26)(H,22,23,24)/t14-/m0/s1
• InChIKey: LYPAFUINURXJSG-AWEZNQCLSA-N
• SMILES: O=C(C1=NN=C(CC2=CC=CC=C2)N1)N[C@@H]3C(N(C)C4=CC=CC=C4OC3)=O

GSK2982772 (CAT: I007102) is a potent and selective inhibitor of receptor-interacting protein 1 (RIP1) kinase, which has emerged as an important kinase involved in regulating inflammation. GSK2982772 specifically targets RIP1 kinase, inhibiting its activity and preventing downstream signaling events associated with inflammatory responses. It has shown excellent activity in blocking TNF-dependent cellular responses and is being developed as a potential treatment for inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis. GSK2982772 is currently undergoing phase II clinical studies to evaluate its efficacy and safety in these indications. Its selective inhibition of RIP1 kinase makes it a promising candidate for the targeted treatment of inflammatory conditions.

Overview of Clinical Research

Originator: GlaxoSmithKline
Class: Anti-inflammatories; Antipsoriatics; Antirheumatics
Mechanism of Action: Immunomodulators; Receptor-interacting protein serine-threonine kinase inhibitors
Orphan Drug Status: No
New Molecular Entity: Yes

Reference

1:J Med Chem. 2017 Feb 23;60(4):1247-1261. doi: 10.1021/acs.jmedchem.6b01751. Epub 2017 Feb 10. Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases.Harris PA,Berger SB,Jeong JU,Nagilla R,Bandyopadhyay D,Campobasso N,Capriotti CA,Cox JA,Dare L,Dong X,Eidam PM,Finger JN,Hoffman SJ,Kang J,Kasparcova V,King BW,Lehr R,Lan Y,Leister LK,Lich JD,MacDonald TT,Miller NA,Ouellette MT,Pao CS,Rahman A,Reilly MA,Rendina AR,Rivera EJ,Schaeffer MC,Sehon CA,Singhaus RR,Sun HH,Swift BA,Totoritis RD,Vossenkämper A,Ward P,Wisnoski DD,Zhang D,Marquis RW,Gough PJ,Bertin J, PMID: 28151659 DOI: 10.1021/acs.jmedchem.6b01751
Abstract: RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and 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. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.