GSK143 dihydrochloride

• CAT Number: I015317
• CAS Number: 2341796-81-2
• Molecular Formula: C17H24Cl2N6O2
• Molecular Weight: 415.32
• Purity: ≥95%
• Synonyms: 2-[[(3R,4R)-3-aminooxan-4-yl]amino]-4-(4-methylanilino)pyrimidine-5-carboxamide;dihydrochloride
• InChI: InChI=1S/C17H22N6O2.2ClH/c1-10-2-4-11(5-3-10)21-16-12(15(19)24)8-20-17(23-16)22-14-6-7-25-9-13(14)18;;/h2-5,8,13-14H,6-7,9,18H2,1H3,(H2,19,24)(H2,20,21,22,23);2*1H/t13-,14+;;/m0../s1
• InChIKey: UEHPBSLIDBDMCZ-WICJZZOFSA-N
• SMILES: CC1=CC=C(C=C1)NC2=NC(=NC=C2C(=O)N)NC3CCOCC3N.Cl.Cl

GSK143 dihydrochloride is an orally active and highly selective spleen tyrosine kinase (SYK) inhibitor with a pIC50 of 7.5. GSK143 dihydrochloride inhibits phosphorylated Erk (pErk: pIC50=7.1)[1]. GSK143 dihydrochloride reduces inflammation and prevents recruitment of immune cells in the intestinal muscularis in mice[2][3].
GSK143 dihydrochloride (compound 20) inhibits ZAP-70 (pIC50=4.7), LCK (pIC50=5.3), LYN (pIC50=5.4), JAK1/2/3 (pIC50=5.8/5.8/5.7), Aurora B (pIC50=4.8), hWB (pIC50=6.6), hERG (pIC50=4.7)[1].
GSK143 dihydrochloride (10-10000 nM; every 24 hours for 3 days) has an IC50 of 323 nM in CLL cells. GSK 143 dihydrochloride (1 μM; 30 mins) abrogates early signalling events including SYK phosphorylation and calcium flux[2].
GSK143 dihydrochloride (0.1-10 μM; for 30 min) reduces cytokine expression in bone marrow derived macrophages in a concentration-dependent manner[3].
GSK143 (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[3].
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[2].
GSK143 (iv of 1 mg/kg; po of 3 mg/kg) has a T1/2 of 4.2 hours, low clearance (16 mL/min/kg), moderate bioavailability of 30% and a Vss of 4.1 L/kg in rats[1].

Reference

[1]. John Liddle, et al. Discovery of GSK143, a Highly Potent, Selective and Orally Efficacious Spleen Tyrosine Kinase Inhibitor. Bioorg Med Chem Lett. 2011 Oct 15;21(20):6188-94.
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[2]. Abraham M Varghese, et al. Highly Selective SYK Inhibitor, GSK143, Abrogates Survival Signals in Chronic Lymphocytic Leukaemia. Br J Haematol. 2018 Sep;182(6):927-930.
 [Content Brief]

[3]. Sjoerd H W van Bree, et al. Inhibition of Spleen Tyrosine Kinase as Treatment of Postoperative Ileus. Gut. 2013 Nov;62(11):1581-90.
 [Content Brief]