AS-605240

2 years -80 in solvent

Orally

RAW264 macrophages

50 mg/kg

8 nM, 8 nM, 8 nM, 8 nM, 8 nM, 8 nM

In RANTES-induced mouse model of peritonitis, AS-605240 reduces neutrophil chemotaxis with ED50 of 9.1 mg/kg. In a alphaCII-induced arthritis, AS-605240 (50 mg/kg) protects against alphaCII-IA symptom. In a mouse model of collagen-induced arthritis, AS-605240 (50 mg/kg) also suppresses joint inflammation and damage. [1] In an obesity-induced diabetes model (ob/ob mice), AS-605240 (10 mg/kg) lowers blood glucose levels, significantly improves both insulin sensitivity and glucose tolerance without affecting body weight. AS-605240 (30 mg/kg) displays more profound effects with slightly less weight gain. Moreover, AS-605240 reduces the abundance of ATMs and the circulating levels of MCP-1. [3]

In vitro PI3K lipid kinase assay, (1) For PI3Kgamma: human PI3Kgamma (100 ng) is incubated at RT with kinase buffer (10 mM MgCl2, 1 mM beta-glycerophosphate, 1 mM DTT, 0.1 mM Na3VO4, 0.1% Na Cholate and 15 uM ATP/100 nCi gamma[33P]ATP, final concentrations) and lipid vesicles containing 18 uM PtdIns and 250 uM of PtdSer (final concentrations), in the presence of AS-605240 or DMSO. Kinase reaction is stopped by adding 250 ug of Neomycin-coated Scintillation Proximity Assay (SPA) beads. (2) For PI3Kalpha, beta, and delta: varying amounts of ATP are incubated with the different purified PI3K isoforms and saturating concentrations of PtdIns. Consequently, IC50 determinations with PI3Kalpha, beta, and delta, to evaluate inhibitor selectivity are performed as follows: 60 ng of PI3Kalpha are incubated at RT with kinase buffer, as described for PI3Kgamma (but containing 89 uM ATP/300 nCi gamma[33P]ATP and no Na Cholate, instead) and lipid vesicles containing 212 uM PtdIns and 58 uM of PtdSer. 100 ng of PI3Kbeta are incubated at RT with kinase buffer (containing 70 uM ATP/300 nCi gamma[33P]ATP, 4 mM MgCl2 and no Na Cholate) and lipid vesicles containing 225 uM PtdIns and 45 uM of PtdSer. 90 ng of PI3Kdelta are incubated with kinase buffer (containing 65 uM ATP/300 nCi gamma[33P]ATP, 1 mM MgCl2, and no Na Cholate) and lipid vesicles containing 100 uM PtdIns and 170 uM of PtdSer. The reactions are stopped after 2 hours.

DMSO 0.4 mg/mL, Water <1 mg/mL, Ethanol <1 mg/mL

(Z)-5-(quinoxalin-6-ylmethylene)thiazolidine-2, 4-dione