(5Z)-5-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione

• ChemBase ID: 5147
• Molecular Formular: C11H5F2NO4S
• Molecular Mass: 285.2235064
• Monoisotopic Mass: 284.99073509
• SMILES: C1(=O)NC(=O)S/C/1=C\c1cc2c(cc1)OC(O2)(F)F
• Canonical SMILES: O=C1NC(=O)/C(=C/c2ccc3c(c2)OC(O3)(F)F)/S1
• InChI: InChI=1S/C11H5F2NO4S/c12-11(13)17-6-2-1-5(3-7(6)18-11)4-8-9(15)14-10(16)19-8/h1-4H,(H,14,15,16)/b8-4-
• InChIKey: SRLVNYDXMUGOFI-YWEYNIOJSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: (5Z)-5-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione
• IUPAC Traditional name: (5Z)-5-[(2,2-difluoro-1,3-benzodioxol-5-yl)methylidene]-1,3-thiazolidine-2,4-dione
• Synonyms: (5E)-5-[(2,2-DIFLUORO-1,3-BENZODIOXOL-5-YL)METHYLENE]-1,3-THIAZOLIDINE-2,4-DIONE; AS604850

Database IDs

• CAS Number: 648449-76-7
• PubChem SID: 99443974; 160968577
• PubChem CID: 5287855

CALCULATED PROPERTIES

JChem

• Acid pKa: 7.402612
• H Acceptors: 4
• H Donor: 1
• LogD (pH = 5.5): 2.8605978
• LogD (pH = 7.4): 2.5711064
• Log P: 2.8659368
• Molar Refractivity: 60.0578 cm^3
• Polarizability: 23.4004 Å^3
• Polar Surface Area: 64.63 Å^2
• Rotatable Bonds: 1
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 1.75
• LOG S: -3.33
• Solubility (Water): 1.33e-01 g/l

PROPERTIES

Safety Information

• Storage Condition: -20°C

Pharmacology Properties

• Target: PI3K

Product Information

• Salt Data: Free Base

DETAILS

DrugBank - DB07503

Drug information: experimental

Selleck Chemicals - S2681

Biological Activity

• Description: AS-604850 is a selective, ATP-competitive PI3Kγ inhibitor with IC50 of 250 nM.
• Targets: PI3Kγ; PI3Kα; PI3Kβ; PI3Kδ
• IC50: 250 nM; 4.5 μM; > 20 μM; > 20 μM ^[1]
• In Vitro: AS-604850 is ATP-competitive PI3Kγ inhibitor with K_i values of 0.18 μM. AS-604850 is isoform selective inhibitor of PI3Kγ with over 30-fold selectivity for PI3Kγ and β, and 18-fold selectivity over PI3Kα. (PI3Kα: IC50 = 4.5 μM, PI3Kγ and β: IC50 > 20μM) AS-604850 is capable of inhibiting C5a-mediated PKB phosphorylation in RAW264 mouse macrophages with an IC50 with 10 μM. AS-604850 blocks MCP-1–mediated chemotaxis in Pik3cg ^+/+ monocytes in a concentration- dependent manner, with an IC50 of 21 mM, but dosn’t affect chemotaxis in Pik3cg^-/- cells, indicating that AS-604850 acts through PI3Kγ. ^[1] AS-604850 diminishes glycochenodeoxycholate (GCDC) induced Akt-phosphorylation and apoptosis in rat hepatocytes. AS-604850 diminishes bile salt-induced apoptosis in HepG2 Ntcp and Huh7-Ntcp cells. ^[2] AS604850 causes a concentration-dependent suppression of chemotactic responses of EoL-1 cells and blood eosinophils to platelet-activating factor (PAF). ^[3]
• In Vivo: AS-604850 reduces RANTES-induced peritoneal neutrophil recruitment with a ED50 of 42.4 mg/kg. In the thioglycollate-induced peritonitis model, oral administration of 10 mg/kg AS-604850 results in a 31% reduction of neutrophil recruitment. ^[1]

Protocol

• Protocol: Kinase Assay ^[1]
• In vitro PI3Kγ Kinase Assay: Human PI3Kγ (100 ng) is incubated at RT with kinase buffer (10 mM MgCl₂, 1 mM β-glycerophosphate, 1 mM DTT, 0.1 mM Na₃VO₄, 0.1% Na Cholate and 15 M ATP/100 nCi γ[^33]ATP, final concentrations) and lipid vesicles containing 18 M PtdIns and 250 M of PtdSer (final concentrations), in the presence of AS-252424 or DMSO. Kinase reaction is stopped by adding 250 g of Neomycin-coated Scintillation Proximity Assay (SPA) beads and preceded.
• Protocol: Cell Assay ^[2]
• Cell Lines: HepG2 Ntcp and Huh7-Ntcp cells
• Concentrations: 2.5 μM
• Incubation Time: 2 - 4 hours
• Methods: Hepatocyte cultures are treated with diluent (DMSO), 25 μM TLC, 250 μM TCDC, 50 μM GCDC, or 50 ng/ml Fas for 2–4 hours HepG2-Ntcp and Huh7-Ntcp cells are treated with DMSO, 20 μM TLC, 75 μM TCDC or GCDC, 200 μM etoposide or 200 ng/ml TNFa plus 28 ng/ml actinomycin D for 2–4 hours. The number of apoptotic cells is determined morphologically using fluorescent staining and expressed as % of cells. Apoptosis is confirmed in human cell lines by determination of caspase-3/-7 activity and in rat hepatocytes by detection of the 17 kDa proteolytic cleavage fragment of caspase-3 by immunoblotting; equal protein loading is monitored by immunoblotting for actin.
• Protocol: Animal Study ^[1]
• Animal Models: RANTES (0.5 mg/kg in 200 ml saline) or thioglycollate (40 ml/kg) are intraperitoneally injected to C3H mice to induce peritonitis mouse models
• Formulation: AS-604850 is dissolved in vehicle (0.5% carboxymethylcellulose/0.25% Tween-20) and adjusted the solution to 10 mL/kg of body weight.
• Doses: 0, 1, 3, 10 or 30 mg/kg for RANTES, 10 mg/kg for thioglycollate
• Administration: Oral administration 30 or 15 minutes before injection of RANTES or thioglycollate

References

• References: [1] Camps M, et al, Nat Med, 2005, 11(9), 936-943.
• References: [2] Hohenester S, et al, J Hepatol, 2010, 53(5), 918-926.
• References: [3] Hasan AM, et al, Int Immunopharmacol, 2010, 10(9), 1017-1021.

REFERENCES

• Camps M, et al, Nat Med, 2005, 11(9), 936-943.
• Hohenester S, et al, J Hepatol, 2010, 53(5), 918-926.
• Hasan AM, et al, Int Immunopharmacol, 2010, 10(9), 1017-1021.