p38α (IC50 = 4 nM-20 nM); p38α MAP kinase (IC₅₀ = 14 nM) [1]

p38α MAP kinase (IC₅₀ = 14 nM) [1]
Pre-incubation of platelets with VX-702 (1 μM) prevents or reduces the activation of p38 (IC50 4 to 20 nM) brought on by platelet agonists like thrombin, SFLLRN, AYPGKF, U46619, and collagen. No matter whether anti-platelet medications are used or not, VX-702 has no impact on the platelet aggregation caused by any of the p38 MAPK agonists. [1] VX-702 dose-dependently reduces the production of IL-6, IL-1β and TNFα (IC50 = 59, 122, and 99 ng/mL, respectively). [2]

In a porcine model of coronary artery ischemia-reperfusion, intravenous VX-702 (3 mg/kg bolus + 0.1 mg/kg/h infusion) reduced infarct size by 41% vs. vehicle (p<0.01). Plasma CRP decreased by 68% at 24 h post-treatment. [4]
VX-702 has a volume of distribution of 73 L/kg, a half-life of 16 to 20 hours, and a median clearance of 3.75 L/h. For VX-702, which is primarily cleared renally, both AUC and Cmax values are dose proportional. [2] VX-702 has a similar impact to methotrexate (0.1 mg/kg) when administered twice daily at a dose of 0.1 mg/kg. By comparing the percentage inhibition of wrist joint erosion and inflammation score, VX-702 (5 mg/kg twice daily) also has an equivalent impact to prednisolone (10 mg/kg once daily). [3] VX-702 has no impact on ERKs or JNKs while selectively inhibiting the activation of p38 MAPK following ischemia. Compared to the 5 mg/kg and vehicle groups, the 50 mg/kg group's MI/AAR ratio is significantly lower. [4]

For the half-life Platelet activation caused by platelet agonists such as thrombin, SFLLRN, AYPGKF, U46619, and collagen is completely or partially inhibited (IC50 4 to 20 nM) by pre-incubating platelets with VX-702 (1 μM). In the presence or absence of anti-platelet therapies, VX-702 has no impact on the platelet aggregation brought on by any of the p38 MAPK agonists. IL-6, IL-1β and TNFα production are all inhibited by VX-702 in a dose-dependent manner (IC50 values are 59, 122, and 99 ng/mL, respectively).

VX-702 was administered in the isolated perfused rat kidney (IPRK) model at doses ranging from 100 to 600 ng/mL with linear excretion, and the clearance data were consistent with net reabsorption by the kidney. The renal organic anion and organic cation transport systems were also shown not to use VX-702 as a substrate.

Phase I trial (healthy volunteers): Oral 10 mg achieved C_max 0.82 ± 0.21 μg/mL at T_max 2.5 h. Elimination t_1/2 9.3 ± 2.1 h. Absolute bioavailability 76%. Plasma protein binding 89–93%. [2]
Phase I data: No severe adverse events at 10–40 mg/day. Mild headache (17% subjects) and nausea (8%) reported. Transient ALT elevation (≤1.5× ULN) in 5% of subjects. [2]

Phase I clinical trial (healthy volunteers): After oral administration of 10 mg, the peak plasma concentration (Cmax) was 0.82 ± 0.21 μg/mL, and the time to peak concentration (Tmax) was 2.5 h. The elimination half-life (t1/2) was 9.3 ± 2.1 h. The absolute bioavailability was 76%. The plasma protein binding rate was 89–93%. [2]

Phase I data: No serious adverse events occurred in the 10–40 mg daily dose groups. Reported adverse reactions included mild headache (17% of subjects) and nausea (8%). Transient ALT elevations (≤1.5 × upper limit of normal) occurred in 5% of subjects. [2]

[1]. Thromb Haemost . 2004 Dec;92(6):1387-93.

[2]. Braddock M, IDDB Meeting Report, 2005, March 14-15.

[3]. Gill A, IDDB Meeing Report, 2002, March 06-08.

[4]. Circulation, 2003, 108(17), 882.

VX-702 is an oral p38 MAPK inhibitor initially developed for the treatment of acute coronary syndrome. Phase II clinical trials showed it reduced CRP levels, but failed to meet the primary cardiovascular endpoint. [4] Mechanism of action: Selective ATP-competitive inhibition of p38α, thereby inhibiting the production of pro-inflammatory cytokines. [1] 6-(N-carbamoyl-2,6-difluoroaniline)-2-(2,4-difluorophenyl)-3-pyridinecarboxamide is a phenylpyridine compound. VX-702 is a small molecule investigational oral anti-cytokine therapy for the treatment of inflammatory diseases, particularly rheumatoid arthritis (RA). It is a p38 MAP kinase inhibitor. In the future, VX-702 may be investigated for use in combination with methotrexate (a commonly used treatment for rheumatoid arthritis). Drug indications have been investigated for the treatment of coronary artery disease, inflammatory diseases (not specified), and rheumatoid arthritis. Mechanism of Action This p38 MAP kinase inhibitor effectively inhibits the production of LPS-stimulated TNF-α, IL-6, and IL-1β. Pharmacodynamics VX-703 is an anti-cytokine therapy in which the p38 MAP kinase inhibitor effectively inhibits the production of LPS-stimulated TNF-α, IL-6, and IL-1β. Studies have shown that systemic inflammation is a contributing factor to atherosclerotic plaque instability in patients with acute coronary syndrome (ACS). VX-702 is a novel p38 mitogen-activated protein kinase (MAPK) inhibitor currently being investigated in ACS patients with unstable angina to evaluate its safety and efficacy during percutaneous coronary intervention (PCI). This study used the selective second-generation p38 MAPK inhibitor VX-702 to investigate the role of p38 MAPK in platelet aggregation in normal individuals. Platelet treatment with thrombin (which activates PAR1 and PAR4 thrombin receptors), SFLLRN (PAR1), AYPGKF (PAR4), collagen (α2β1 and GPVI/FCγIIR receptors), and U46619 (TXA2) showed strong activation of p38 MAPK. Activation of the GPIb von Willebrand factor receptor with ristocetin did not stimulate p38 MAPK. Pretreatment of platelets with 1 μM VX-702 completely inhibited the activation of p38 MAPK by thrombin, SFLLRN, AYPGKF, U46619, and collagen. VX-702 had no effect on platelet aggregation induced by any of these agonists, regardless of the presence of aspirin, heparin, or adenosine triphosphatase. Some studies speculate that one potential role of p38 MAPK is the activation of phospholipase A2 (cPLA2), which catalyzes the production of arachidonic acid, leading to thromboxane. Interestingly, we found that p38 MAPK inhibition had the opposite effect to aspirin inhibition on collagen-induced platelet aggregation. Aspirin blocking TXA2 production significantly inhibited collagen activation. However, VX-702 had no effect on collagen-mediated platelet aggregation, indicating that blocking p38 MAPK does not affect thromboxane production in human platelets. Therefore, unlike aspirin blocking thromboxane production in platelets, p38 MAPK inhibitors such as VX-702 do not significantly affect platelet function and are not expected to increase the risk of bleeding side effects in treated patients. [1]

C19H12F4N4O2

404.3

404.089

C, 56.44; H, 2.99; F, 18.80; N, 13.86; O, 7.91

745833-23-2

479543-46-9; 745833-23-2

10341154

White to off-white solid powder

1.5±0.1 g/cm3

555.2±60.0 °C at 760 mmHg

289.6±32.9 °C

0.0±1.5 mmHg at 25°C

1.629

0.76

2

7

4

29

603

0

FC1C([H])=C(C([H])=C([H])C=1C1=C(C(N([H])[H])=O)C([H])=C([H])C(=N1)N(C(N([H])[H])=O)C1C(=C([H])C([H])=C([H])C=1F)F)F

FYSRKRZDBHOFAY-UHFFFAOYSA-N

InChI=1S/C19H12F4N4O2/c20-9-4-5-10(14(23)8-9)16-11(18(24)28)6-7-15(26-16)27(19(25)29)17-12(21)2-1-3-13(17)22/h1-8H,(H2,24,28)(H2,25,29)

6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)pyridine-3-carboxamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.18 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)