生物活性

• 描述GSK2982772 is an optimized RIP1 kinase inhibitor with IC50 value of 1nM in a FP/ADP-Glo assay, which is a clinical candidate currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. It inhibited U937 cell viability with IC50 value of 6.3nM. Treatment with GSK2982772 at 300nM overnight reduced IL-1β and IL-6 production by ~60% in human explant samples taken from ulcerative colitis patients. GSK2982772 dosed orally 15 min prior to TNF and showed 68, 80 and 87% protection from temperature loss over 6 h, at doses of 3, 10, and 50 mg/kg, respectively. It showed 13, 63, and 93% protection from temperature loss over 3h in the corresponding TNF/zVAD model^[2].
• 作用机制GSK2982772 packed against 2 β-strands defined by Leu90-Val91-Met92 and Ile43-Met44-Lys45 of RIP1 kinase, siting deeper in the ATP binding pocket and occupying an allosteric lipophilic pocket at the back through the benzyl group.^[2]

• 动物研究
  剂量	Mice: 50 mg/kg[1] (p.o.); 3 mg/kg - 50 mg/kg[1] (i.v.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Rats[1] Monkeys[1] Dose 1.1 mg/kg (i.v.) 2.1 mg/kg (p.o.) 1.2 mg/kg (i.v.) 1.9 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. F 110 ± 20% (p.o.) 86 ± 6% (p.o.) T1/2 3.9 ± 0.7 h (i.v.) 6.5 ± 1.0 h (i.v.) Tmax 0.25 ± 0.0 h (p.o.) 1.8 ± 1.1 h (p.o.) CL 17 ± 5 ml/min/kg (i.v.) 10 ± 3 ml/min/kg (i.v.) Cmax 810 ± 160 μg/ml (p.o.) 720 ± 240 μg/ml (p.o.) Vss 2.7 ± 0.6 L/kg (i.v.) 2.2 ± 0.9 L/kg (i.v.) AUC 2.3 ± 0.8 μg·h/ml (p.o.) 2.9 ± 0.8 μg·h/ml (p.o.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02903966	Colitis, Ulcerative	Phase 2	Recruiting	May 7, 2019	United States, California ... more >> GSK Investigational Site Recruiting Moreno Valley, California, United States, 92555 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Terminated Oceanside, California, United States, 92056 GSK Investigational Site Recruiting San Diego, California, United States, 92115 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    United States, Louisiana GSK Investigational Site Not yet recruiting Marrero, Louisiana, United States, 70072 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    United States, Michigan GSK Investigational Site Recruiting Chesterfield, Michigan, United States, 48047 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    United States, New York GSK Investigational Site Recruiting Great Neck, New York, United States, 11021 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    United States, Washington GSK Investigational Site Not yet recruiting Seattle, Washington, United States, 98195 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    Germany GSK Investigational Site Recruiting Ulm, Baden-Wuerttemberg, Germany, 89081 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Not yet recruiting Frankfurt, Hessen, Germany, 60431 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Not yet recruiting Kiel, Schleswig-Holstein, Germany, 24105 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    Netherlands GSK Investigational Site Recruiting Amsterdam, Netherlands, 1105 AZ Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    Poland GSK Investigational Site Recruiting Katowice, Poland, 40-660 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Recruiting Ksawerow, Poland, 95-054 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Not yet recruiting Wroclaw, Poland Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    Russian Federation GSK Investigational Site Recruiting Rostov-on-Don, Russian Federation, 344091 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Recruiting St Pertersburg, Russian Federation, 196247 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Not yet recruiting Stavropol, Russian Federation, 355018 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Recruiting Ufa, Russian Federation, 450071 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    Sweden GSK Investigational Site Recruiting Stockholm, Sweden, SE-171 76 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Recruiting Stockholm, Sweden, SE-182 88 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Recruiting Uppsala, Sweden, SE-752 37 Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    United Kingdom GSK Investigational Site Recruiting Stockport, Cheshire, United Kingdom, SK2 7JE Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Recruiting Belfast, United Kingdom, BT16 1RH Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Recruiting Dudley, United Kingdom, DY1 2HQ Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com    GSK Investigational Site Not yet recruiting Edgbaston, Birmingham, United Kingdom, B15 2GW Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com    Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com Collapse <<
  NCT02858492	Arthritis, Rheumatoid	Phase 1 Phase 2	Completed	-	Germany ... more >> GSK Investigational Site Rendsburg, Schleswig-Holstein, Germany, 24768 GSK Investigational Site Jena, Thueringen, Germany, 07740 GSK Investigational Site Berlin, Germany, 10117 Italy GSK Investigational Site Roma, Lazio, Italy, 00168 GSK Investigational Site Verona, Veneto, Italy, 37134 Poland GSK Investigational Site Bialystok, Poland, 15-879 GSK Investigational Site Elblag, Poland, 82-300 GSK Investigational Site Krakow, Poland, 31-513 GSK Investigational Site Swidnik, Poland, 21-040 GSK Investigational Site Warsaw, Poland, 04-305 Russian Federation GSK Investigational Site Ulyanovsk, Russian Federation, 432063 GSK Investigational Site Yaroslavl, Russian Federation, 150030 Spain GSK Investigational Site Málaga, Andalucia, Spain, 29004 GSK Investigational Site Barcelona, Spain, 08036 GSK Investigational Site Coruña, Spain, 15006 GSK Investigational Site Vitoria - Gasteiz, Spain, 01009 United Kingdom GSK Investigational Site Southampton, Hampshire, United Kingdom, SO16 6YD GSK Investigational Site Southampton, Hampshire, United Kingdom, SO16 6 GSK Investigational Site Cardiff, United Kingdom, CF14 4XW GSK Investigational Site London, United Kingdom, W12 0NN GSK Investigational Site London, United Kingdom, W12 0N GSK Investigational Site Oxford, United Kingdom, OX3 7HE Collapse <<
  NCT02776033	Psoriasis	Phase 2	Completed	-	Canada, Ontario ... more >> GSK Investigational Site Markham, Ontario, Canada, L3P1X2 GSK Investigational Site Peterborough, Ontario, Canada, K9J 5K2 GSK Investigational Site Waterloo, Ontario, Canada, N2J 1C4 Canada, Quebec GSK Investigational Site Montreal, Quebec, Canada, H2K 4L5 Collapse <<

• 更多
• 参考文献

• [1] Harris PA, Berger SB, et al. Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases. J Med Chem. 2017 Feb 23;60(4):1247-1261.

  [2] 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. Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases. J Med Chem. 2017 Feb 23;60(4):1247-1261. doi: 10.1021/acs.jmedchem.6b01751. Epub 2017 Feb 10. PMID: 28151659.