VX-745

VX-745, is highly potent and selective p38α inhibitor (IC50 = 10 nM). VX-745 blocks TNFα production in LPS-stimulated HWB in vitro (IC50 = 177 nM). VX-745 displays excellent enzyme activity and selectivity, has a favorable pharmacokinetic profile, and demonstrates good in vivo activity in models of inflammation.

Product information

CAS Number: 209410-46-8

Molecular Weight: 436.26

Formula: C19H9Cl2F2N3OS

Synonym:

VRT-031745

VD-31745

Neflamapimod

Chemical Name: 5-(2, 6-Dichlorophenyl)-2-(2, 4-difluorophenylsulfanyl)-6H-pyrimido[3, 4-b]pyridazin-6-one

Smiles: O=C1N=CN2N=C(C=CC2=C1C1C(Cl)=CC=CC=1Cl)SC1=CC=C(F)C=C1F

InChiKey: VEPKQEUBKLEPRA-UHFFFAOYSA-N

InChi: InChI=1S/C19H9Cl2F2N3OS/c20-11-2-1-3-12(21)17(11)18-14-5-7-16(25-26(14)9-24-19(18)27)28-15-6-4-10(22)8-13(15)23/h1-9H

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO: 15 mg/mL(34.38 mM). Water: Insoluble.

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

In Vitro:

VX-745 selectively inhibits p38α and p38β MAPK with IC50 of 10 nM and 220 nM, respectively, but not p38γ MAPK and a large panel of other kinases, with IC50 larger than 20 µM. In a human peripheral blood mononuclear cell (PBMC) assay, VX-745 provides IC50 of 56 and 52 nM for IL-1β and TNFα, respectively. VX-745 blocks IL-6 and IL-8 production induced by IL-1 and TNFα, and COX-2 synthesis mediated by LPS and IL-1β. [1-3] VX-745 (60 nM-20 µM) inhibits IL-6 and VEGF secretion in bone marrow stromal cells (BMSCs), without affecting their viability. VX-745 also inhibits TNF-α-induced IL-6 secretion in BMSCs. VX-745 inhibits both multiple myeloma (MM) cell proliferation and IL-6 secretion in BMSCs triggered by adherence of MM cells to BMSCs, suggesting that VX-745 can inhibit paracrine multiple myeloma (MM) cell growth in the BM milieu and overcome cell adhesion-related drug resistance. [4]

In Vivo:

VX-745 is effective against adjuvant-induced arthritis (AA) in the rat with ED50 of 5 mg/kg. Histological scores for VX-745 in AA rats are 93% inhibition of bone resorption and 56% inhibition of inflammation. In the classical cartilage-induced arthritis model, VX-745 exhibits a dose-responsive decrease in severity score. [1-3] In a type II collagen-induced arthritis (CIA) mice model, VX-745 (2.5, 5, and 10 mg/kg) has 27%, 31%, and 44% improvement in the inflammatory scores, respectively, when compared to vehicle-treated mice. In addition, histological scores show a 32-39% protection of bone and cartilage erosion by VX-745. [5]

References:

1. Decicco C, et al. American Chemical Society, 2000, IDDB3.
2. Haddad JJ, Curr Opin Investig Drugs, 2001, 2(8), 1070-1076.
3. Salituro FG, et al. 27th National Medicinal Chemistry Symposium
4. Hideshima T, et al. Blood, 2003, 101(2), 703-705.
5. Duffy JP, et al. ACS Med Chem Lett, 2011, 2(10), 758-763.

Products are for research use only. Not for human use.