GSK2981278

GSK2981278
Clinical data
Drug class	RORγ agonist
Identifiers
	IUPAC name N-(4-ethylphenyl)-3-(hydroxymethyl)-N-(2-methylpropyl)-4-(oxan-4-ylmethoxy)benzenesulfonamide;
CAS Number	1474110-21-8;
PubChem CID	89875987;
IUPHAR/BPS	9661;
DrugBank	DB16319;
ChemSpider	39625826;
UNII	L49V5G013I;
ChEMBL	ChEMBL4225088;
Chemical and physical data
Formula	C25H35NO5S
Molar mass	461.62 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CCC1=CC=C(C=C1)N(CC(C)C)S(=O)(=O)C2=CC(=C(C=C2)OCC3CCOCC3)CO;
	InChI InChI=1S/C25H35NO5S/c1-4-20-5-7-23(8-6-20)26(16-19(2)3)32(28,29)24-9-10-25(22(15-24)17-27)31-18-21-11-13-30-14-12-21/h5-10,15,19,21,27H,4,11-14,16-18H2,1-3H3; Key:LZLBRISQTJVZNP-UHFFFAOYSA-N;

GSK2981278 is a drug which acts as a potent and selective inverse agonist of the receptor RAR-related orphan receptor gamma (RORγ). It has anti-inflammatory effects mediated by blocking production of various inflammatory mediators such as IL-1β, IL-6, IL-17 and TNFα, and was researched for the treatment of inflammatory conditions such as psoriasis, though it showed disappointing results in human clinical trials due to poor pharmacokinetic properties. However, it continues to be widely used for basic research into the function of RORγ and as a lead compound for the development of related drugs.^[1]^[2]^[3]^[4]^[5]^[6]^[7]

References

↑ Kang EG, Wu S, Gupta A, von Mackensen YL, Siemetzki H, Freudenberg JM, et al. (June 2018). "A phase I randomized controlled trial to evaluate safety and clinical effect of topically applied GSK2981278 ointment in a psoriasis plaque test". The British Journal of Dermatology. 178 (6): 1427–1429. doi:10.1111/bjd.16131. PMID 29150844.
↑ Chen L, Su M, Wu XZ, Wang DZ, Kang YY, Wang CG, et al. (5 February 2022). "Discovery of 2H-chromone-4-one based sulfonamide derivatives as potent retinoic acid receptor-related orphan receptor γt inverse agonists". European Journal of Medicinal Chemistry. 229 114065. doi:10.1016/j.ejmech.2021.114065. PMID 34971876.
↑ Morioka N, Tsuruta M, Masuda N, Yamano K, Nakano M, Kochi T, et al. (21 August 2023). "Inhibition of Nuclear Receptor Related Orphan Receptor γ Ameliorates Mechanical Hypersensitivity Through the Suppression of Spinal Microglial Activation". Neuroscience. 526: 223–236. doi:10.1016/j.neuroscience.2023.07.002. PMID 37419402.
↑ Qi L, Ping YN, Sun SS, Xu R, Zhou XR (December 2024). "Discovery of novel and potent sulfonamide derivatives as orally available drug for psoriasis". Bioorganic Chemistry. 153 107853. doi:10.1016/j.bioorg.2024.107853. PMID 39396455.
↑ Sun SL, Xu HJ, Jiang XL, Zhou J, Shi W, Wang XJ, et al. (28 November 2024). "Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis". Journal of Medicinal Chemistry. 67 (22): 20315–20342. doi:10.1021/acs.jmedchem.4c01727. PMID 39546350.
↑ Lv L, Chen B, Gao Y, Sun N, Li W, Fu W (12 December 2024). "Discovery of Novel N-Sulfonamide-tetrahydroquinolines as Potent Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists for the Treatment of Psoriasis". Journal of Medicinal Chemistry. 67 (23): 21400–21420. doi:10.1021/acs.jmedchem.4c02318. PMID 39611350.
↑ Chen Y, Man-Tak Chu J, Liu JX, Duan YJ, Liang ZK, Zou X, et al. (January 2025). "Double negative T cells promote surgery-induced neuroinflammation, microglial engulfment and cognitive dysfunction via the IL-17/CEBPβ/C3 pathway in adult mice". Brain, Behavior, and Immunity. 123: 965–981. doi:10.1016/j.bbi.2024.10.029. PMID 39491565.

[1] Kang EG, Wu S, Gupta A, von Mackensen YL, Siemetzki H, Freudenberg JM, et al. (June 2018). "A phase I randomized controlled trial to evaluate safety and clinical effect of topically applied GSK2981278 ointment in a psoriasis plaque test". The British Journal of Dermatology. 178 (6): 1427–1429. doi:10.1111/bjd.16131. PMID 29150844.

[2] Chen L, Su M, Wu XZ, Wang DZ, Kang YY, Wang CG, et al. (5 February 2022). "Discovery of 2H-chromone-4-one based sulfonamide derivatives as potent retinoic acid receptor-related orphan receptor γt inverse agonists". European Journal of Medicinal Chemistry. 229 114065. doi:10.1016/j.ejmech.2021.114065. PMID 34971876.

[3] Morioka N, Tsuruta M, Masuda N, Yamano K, Nakano M, Kochi T, et al. (21 August 2023). "Inhibition of Nuclear Receptor Related Orphan Receptor γ Ameliorates Mechanical Hypersensitivity Through the Suppression of Spinal Microglial Activation". Neuroscience. 526: 223–236. doi:10.1016/j.neuroscience.2023.07.002. PMID 37419402.

[4] Qi L, Ping YN, Sun SS, Xu R, Zhou XR (December 2024). "Discovery of novel and potent sulfonamide derivatives as orally available drug for psoriasis". Bioorganic Chemistry. 153 107853. doi:10.1016/j.bioorg.2024.107853. PMID 39396455.

[5] Sun SL, Xu HJ, Jiang XL, Zhou J, Shi W, Wang XJ, et al. (28 November 2024). "Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis". Journal of Medicinal Chemistry. 67 (22): 20315–20342. doi:10.1021/acs.jmedchem.4c01727. PMID 39546350.

[6] Lv L, Chen B, Gao Y, Sun N, Li W, Fu W (12 December 2024). "Discovery of Novel N-Sulfonamide-tetrahydroquinolines as Potent Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists for the Treatment of Psoriasis". Journal of Medicinal Chemistry. 67 (23): 21400–21420. doi:10.1021/acs.jmedchem.4c02318. PMID 39611350.

[7] Chen Y, Man-Tak Chu J, Liu JX, Duan YJ, Liang ZK, Zou X, et al. (January 2025). "Double negative T cells promote surgery-induced neuroinflammation, microglial engulfment and cognitive dysfunction via the IL-17/CEBPβ/C3 pathway in adult mice". Brain, Behavior, and Immunity. 123: 965–981. doi:10.1016/j.bbi.2024.10.029. PMID 39491565.

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GSK2981278

References