GSK143 dihydrochloride (C09-1135-068)

GSK143 dihydrochloride is an orally active and highly selective spleen tyrosine kinase (SYK) inhibitor with a pIC 50 of 7.5. GSK143 dihydrochloride inhibits phosphorylated Erk (pErk: pIC 50 =7.1) GSK143 dihydrochloride reduces inflammation and prevents recruitment of immune cells in the intestinal muscularis in miceIn VitroGSK143 dihydrochloride (compound 20) inhibits ZAP-70 (pIC 50 =4.7), LCK (pIC 50 =5.3), LYN (pIC 50 =5.4), JAK1/2/3 (pIC 50 =5.8/5.8/5.7), Aurora B (pIC 50 =4.8), hWB (pIC 50 =6.6), hERG (pIC 50 =4.7). GSK143 dihydrochloride (10-10000 nM; every 24 hours for 3 days) has an IC 50 of 323 nM in CLL cells. GSK 143 dihydrochloride (1 μM; 30 mins) abrogates early signalling events including SYK phosphorylation and calcium flux. GSK143 dihydrochloride (0.1-10 μM; for 30 min) reduces cytokine expression in bone marrow derived macrophages in a concentration-dependent manner. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Viability AssayCell Line: Chronic lymphocytic leukaemia (CLL) cells Concentration: 10, 100, 1000, 10000 nM Incubation Time: Every 24 hours for 3 days Result: Had an IC 50 of 323 nM.In VivoGSK143 (0.1-10 mg/kg; orally; 1.5 hours) reduces inflammation and prevents recruitment of immune cells in the intestinal muscularis of 1 mg/kg. GSK143 (3, 10, 30, 100 mg/kg; oral; 1 hour before ovalbumin challenge) reduces the cutaneous reverse passive Arthus reaction in a dose dependent manner by approximately 50% and 70% at 10 mg/kg and 30 mg/kg, respectively. GSK143 (iv of 1 mg/kg; po of 3 mg/kg) has a T 1/2 of 4.2 hours, low clearance (16 mL/min/kg), moderate bioavailability of 30% and a V ss of 4.1 L/kg in rats . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Wild type C57NL/BL6 mice, 10-12 weeks oldDosage: 0.1, 1, 3, 10 mg/kg Administration: Orally; 1.5 hours before intestinal manipulation (IM) Result: Reduced inflammation and prevented recruitment of immune cells in the intestinal muscularis. Animal Model: Male CD rats (175-200 g) Dosage: 1 mg/kg of iv; 3 mg/kg of po (Pharmacokinetic Analysis) Administration: IV or PO Result: Had a T 1/2 of 4.2 hours, low clearance (16 mL/min/kg), moderate bioavailability of 30% and a V ss of 4.1 L/kg.Form:SolidIC50& Target:pIC50: 7.5 (SYK) and 7.1 (pErk). Specification: 0.99 Molecular Formula: C17H24Cl2N6O2 Molecular Weight: 415.32