GSK2981278 / GSK - LARVOL DELTA

Discovery of Novel N-Sulfonamide-tetrahydroquinolines as Potent Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) Inverse Agonists for the Treatment of Psoriasis. (PubMed, J Med Chem) - "The ointment of 5a was assessed in the mouse model, where it demonstrated significant antipsoriatic effects, superior to 13 and comparable to the positive control GSK2981278, without obvious toxicity. Furthermore, we elucidated molecular mechanism of action for inverse agonist 5a and agonist 1e by means of molecular dynamics (MD) simulation. In summary, 5a holds great promise as a novel antipsoriatic drug candidate."

Journal • Dermatology • Immunology • Psoriasis

Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis. (PubMed, J Med Chem) - "(R)-D4, the eutomer of D4, matched or exceeded GSK2981278's therapeutic effects at lower doses, with no adverse effects observed after 2 weeks of administration. These results position (R)-D4 as a promising and orally bioavailable candidate for Th17-mediated autoimmune disease treatment."

Journal • Dermatology • Immunology • Inflammatory Arthritis • Psoriasis • Rheumatoid Arthritis • Rheumatology

Double negative T cells promote surgery-induced neuroinflammation, microglial engulfment and cognitive dysfunction via the IL-17/CEBPβ/C3 pathway in adult mice. (PubMed, Brain Behav Immun) - "Postoperative IL-17 specific inhibitor GSK2981278 administration or preoperatively conditional CEBPβ knock-down by AAV9 viral vector were then applied to evaluate the effect of inhibiting IL-17 signaling pathway on postoperative C3 expression and cognitive performance...Both inhibition of IL-17 or knock-down of CEBPβ significantly suppressed C3 expression, synaptic engulfment by microglia and attenuated cognitive impairment. These findings indicate that DNTs promote postoperative neuroinflammation and cognitive impairment via the IL-17/CEBPβ/C3 pathway and targeting this IL-17 axis could be a potential therapeutic strategy to ameliorate postoperative neuroinflammation and cognitive impairment."

Journal • Preclinical • Surgery • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Immunology • Inflammation • Vascular Neurology • CD4 • CD8 • IL17A

Discovery of novel and potent sulfonamide derivatives as orally available drug for psoriasis. (PubMed, Bioorg Chem) - "b14 had greatly improved In Vitro metabolic stability (T1/2 = 36.2 min) compared to GSK2981278 (T1/2 = 0.8 min). Oral dosing of compound b14 resulted in a dose-dependent suppression of IL-17A cytokine levels within a murine model of imiquimod-induced skin inflammation, underscoring its potential as a therapeutic intervention."

Journal • Dermatitis • Dermatology • Immunology • Inflammation • Psoriasis • IL17A

Inhibition of nuclear receptor RORγ ameliorates mechanical hypersensitivity through the suppression of spinal microglial activation. (PubMed, Neuroscience) - "Treatment of cultured microglia with specific RORγ inverse agonists, SR2211 or GSK2981278, significantly suppressed lipopolysaccharide (LPS)-induced mRNA expression of pronociceptive molecules interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF)...In addition, intrathecal administration of SR2211 significantly ameliorated established mechanical hypersensitivity and upregulation of Iba1 immunoreactivity in the spinal dorsal horn of male mice following peripheral sciatic nerve injury. The current findings demonstrate that blockade of RORγ in spinal microglia exerts anti-inflammatory effects, and that RORγ may be an appropriate target for the treatment of chronic pain."

Journal • Immunology • Inflammation • Neuralgia • Oncology • Pain • IL1B • IL6 • TNFA

Melatonin Nuclear Receptors Mediate Green-and-Blue-Monochromatic-Light-Combinations-Inhibited B Lymphocyte Apoptosis in the Bursa of Chickens via Reducing Oxidative Stress and Nfκb Expression. (PubMed, Antioxidants (Basel)) - "Moreover, these responses were abrogated by RORα agonist SR1078 but were mimicked by RORα antagonist SR3335 or RORγ antagonist GSK2981278. In addition, p65 antagonist BAY reversed RORα/RORγ-mediated G→B-inhibited bursal B lymphocyte apoptosis. Overall, we concluded that melatonin nuclear RORα/RORγ mediates G→B-inhibited bursal B lymphocyte apoptosis via reducing oxidative stress and Nfκb expression."

Journal • CASP3 • IFNG • IL10 • IL6 • RELA • TNFA

Discovery of 2H-chromone-4-one based sulfonamide derivatives as potent retinoic acid receptor-related orphan receptor γt inverse agonists. (PubMed, Eur J Med Chem) - "Starting from the reported GSK2981278 (Phase II), we structurally modified and synthesized a series of 2H-chromone-4-one based sulfonamide derivatives as novel RORγt inverse agonists, which significantly improved their human metabolic stabilities while maintaining a potent RORγt inverse agonist profile...During in vivo studies, oral administration of compound c9 exhibited a robust and dose-dependent inhibition of IL-17A cytokine expression and significantly lessened the skin inflammatory symptoms in the mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that c9 can suitably occupy the active pocket, and the introduction of the morpholine pyridine group can interact with Leu396, His479, and Cys393. Thus, compound c9 was selected as a preclinical compound for treating Th17-driven autoimmune diseases."

Journal • Dermatitis • Immunology • Inflammation • IL17A

Discovery of Chromane-6-Sulfonamide Derivative as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist. (PubMed, J Med Chem) - "Using GSK2981278 (phase II) as a starting point, we engineered structural modifications that significantly improved the activity and pharmacokinetic profile. In animal studies, oral administration of compound d3 showed a robust and dose-dependent inhibition of the IL-17A cytokine expression in a mouse imiquimod-induced skin inflammation model. Docking analysis of the binding mode revealed that the compound d3 occupied the active pocket suitably. Thus, compound d3 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases."

Journal • Dermatitis • Immunology • Inflammation • Oncology • CD8 • IL17A

An Overview on Promising Nanotechnological Approaches for the Treatment of Psoriasis. (PubMed, Recent Pat Nanotechnol) - "The new trends in nano technology are marked by subsequent changes in the pharmaceutical research field. To safeguard the research works in research field various patents have been introduced such as Glaxo Smith Kline (GSK 2981278) - RORγ antagonist etc. The causes, pathophysiology and the herbal plants that are used in treating the disease are also discussed."

Journal

A Phase I Randomised Controlled Trial to Evaluate Safety and Clinical Effect of Topically Applied GSK2981278 Ointment in a Psoriasis Plaque Test. (PubMed, Br J Dermatol) - "has identical ligand-binding domains as ROR?t(2) ; consequently, compounds targeting ROR? are also expected to modulate Th17 cell activity."

Clinical • Journal • P1 data