p38α (IC50 = 4 nM-20 nM)

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]

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.

[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.

6-(N-carbamoyl-2,6-difluoroanilino)-2-(2,4-difluorophenyl)-3-pyridinecarboxamide is a phenylpyridine.
VX-702 is a small molecule investigational oral anti-cytokine therapy for treatment of inflammatory diseases, specifically rheumatoid arthritis (RA). It acts as a p38 MAP kinase inhibitor. In the future, VX-702 may be investigated for combination with methotrexate, a commonly used therapy for RA.

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Drug Indication
Investigated for use/treatment in coronary artery disease, inflammatory disorders (unspecified), and rheumatoid arthritis.

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Mechanism of Action
This p38 MAP kinase inhibitor effectively inhibits LPS-stimulated TNF|[alpha]|, IL-6 and IL-1|[beta]| production.

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Pharmacodynamics
VX-703 is an anti-cytokine therapy in which p38 MAP kinase inhibitor effectively inhibits LPS-stimulated TNF|[alpha]|, IL-6 and IL-1|[beta]| production.

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Systemic inflammation has been shown to be a contributing factor to the instability of atherosclerotic plaques in patients with acute coronary syndromes (ACS). VX-702, a novel p38 mitogen-activated protein kinase (MAPK) inhibitor, is currently under investigation in ACS patients with unstable angina to evaluate its safety and efficacy during percutaneous coronary intervention (PCI). The role of p38 MAPK in platelet aggregation of normal individuals was examined using the selective second generation p38 MAPK inhibitor VX-702. Treatment of platelets with thrombin (activates PAR1 and PAR4 thrombin receptors), SFLLRN (PAR1), AYPGKF (PAR4), collagen (alpha2beta1 and GPVI/FCgammaIIR receptors) and U46619 (TXA(2)) resulted in strong activation of p38 MAPK. Activation of the GPIb von Willebrand factor receptor with ristocetin did not stimulate p38 MAPK. Pre-treatment of platelets with 1 microM VX-702 completely inhibited activation of p38 MAPK by thrombin, SFLLRN, AYPGKF, U46619, and collagen. There was no effect of VX-702 on platelet aggregation induced by any of the agonists in the presence or absence of aspirin, heparin or apyrase. It has been postulated that a potential role of p38 MAPK is to activate phospholipase A(2) (cPLA(2)) which catalyses formation of arachidonic acid leading to production of thromboxane. Interestingly, we show contrasting effects of p38 MAPK inhibition as compared to aspirin inhibition on platelet aggregation in response to collagen. Blockade of TXA(2) production by aspirin results in significant inhibition of collagen activation. However,VX-702 has no effect on collagen-mediated platelet aggregation, suggesting that blocking p38 MAPK does not effect thromboxane production in human platelets. Therefore, unlike aspirin blockade of thromboxane production in platelets, p38 MAPK inhibitors such as VX-702 do not significantly affect platelet function and would not be expected to contribute to an elevated 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

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.)