Description
UNC2881 is an inhibitor of Mer (IC
50 = 4.3 nM), a member of the TAM family of receptor tyrosine kinases. It is selective for Mer over the remaining TAM family members Axl and TYRO3 (IC
50s = 360 and 250 nM, respectively). UNC2881 inhibits phosphorylation of Mer in 697 B-ALL acute lymphoblastic leukemia cells (IC
50 = 21.9 nM). It inhibits platelet aggregation and ATP release induced by type I equine fibrillar collagen in isolated human platelet-rich plasma when used at a concentration of 3 μM.
in vivo
UNC2881 (3 mg/kg; p.o.; single dose) has high systemic clearance (94.5 mL/min/kg) and 14% oral bioavailability, displays terminal half-life of 0.80 h[1].
UNC2881 (3 mg/kg; i.v.; injected with VSV on days -3, -2, -1, and 0) limits Mertk signaling, and promotes the antiviral immune response, reducing the viral replication of vesicular stomatitis virus (VSV) in infected mice[2].
Pharmacokinetics of UNC2881 in mice[1]
| Route | Dose (mg/kg) | T1/2 (h) | Tmax (h) | Cmax (ng/mL) | AUClast (ng·h/mL) | CLobs (mL/min) | Vss (L/kg) | F (%) |
| IV | 3 | 0.8 | | 2609 | 527 | 94.5 | 1.65 | |
| PO | 3 | | 0.30 | 90.0 | 71.7 | | | 14 |
| Animal Model: | C57BL/6 mice (7-10 weeks old)[2] |
| Dosage: | 3 mg/kg |
| Administration: | Intravenous injection; infected with 2×108 PFU vesicular stomatitis virus (VSV) (i.v.) on days -3, -2, -1, and 0 |
| Result: | Reduced VSV replication in spleen, liver, kidney, lung. |
References
[1]. zhang w, mciver al, stashko ma, et al. discovery of mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis. j med chem, 2013, 56(23): 9693-9700.
