Biological activity

VX-702 is a highly selective p38α MAPK inhibitor, 14-fold more potent against p38α than against p38β. Phase 2.

Description

VX-702 is a third generation inhibitor of p38 mitogen-activated protein (MAP) kinases, binding to both p38α and p38β (K_d = 3.7 and 17 nM, respectively) in an ATP-competitive fashion. It inhibits IL-6, IL-1β, and TNF-α production in LPS-primed blood with IC₅₀ values of 59, 122, and 99 ng/ml, respectively. VX-702, at 1 μM, inhibits activation of p38 in platelets by thrombin, U-46619 , or collagen but does not block platelet aggregation in response to collagen. Although orally active, VX-702 provides only transient suppression of biomarkers of inflammation in ongoing rheumatoid arthritis.

Uses

VX-702 is a third generation inhibitor of p38 mitogen-activated protein (MAP) kinases, binding to both p38α and p38β (Kd = 3.7 and 17 nM, respectively) in an ATP-competitive fashion. It inhibits IL-6, IL-1β, and TNF-α production in LPS-primed blood with IC50 values of 59, 122, and 99 ng/ml, respectively. VX-702, at 1 μM, inhibits activation of p38 in platelets by thrombin, U-46619 , or collagen but does not block platelet aggregation in response to collagen. Although orally active, VX-702 provides only transient suppression of biomarkers of inflammation in ongoing rheumatoid arthritis.[Cayman Chemical]

Uses

VX-702 is a p38 mitogen-activated protein kinase (MAPK) inhibitor. VX-702 had no effect on platelet aggregation induced by any of the p38 MAPK agonists. VX-702 has potential use in the treatment of inflammation, rheumatoid arthritis and cardiovascular diseases.

Definition

ChEBI: 6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)-3-pyridinecarboxamide is a phenylpyridine.

in vivo

storage

+4°C

References

[1] DAVID M. GOLDSTEIN*. Selective p38α Inhibitors Clinically Evaluated for the Treatment of Chronic Inflammatory Disorders[J]. Journal of Medicinal Chemistry, 2009, 53 6: 2345-2353. DOI:10.1021/jm9012906
[2] ATHAN KULIOPULOS  Lidija C  Ramon Mohanlal. Effect of selective inhibition of the p38 MAP kinase pathway on platelet aggregation.[J]. Thrombosis and haemostasis, 2004, 92 6: 1387-1393. DOI:10.1160/th04-03-0187
[3] NEMANJA DAMJANOV  George T S G  Robert S Kauffman. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: Results of two randomized, double-blind, placebo-controlled clinical studies?[J]. Arthritis & Rheumatology, 2009, 60 5: 1232-1241. DOI:10.1002/art.24485
[4] DING C. Drug evaluation: VX-702, a MAP kinase inhibitor for rheumatoid arthritis and acute coronary syndrome.[J]. Current opinion in investigational drugs, 2006, 7 11: 1020-1025.
[5] ANDREY SKRIPCHENKO. An inhibition of p38 mitogen activated protein kinase delays the platelet storage lesion.[J]. PLoS ONE, 2013: e70732. DOI:10.1371/journal.pone.0070732