LY2562175 - FXR Agonist - MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemELY2562175Cat. No.: HY-103704CAS No.: 1103500-20-4分式: CHClNO分量: 540.44作靶點(diǎn): FXR作通路: Metabolic Enzyme/Protease儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 62.5 mg/mL (115.65 mM; Need ultras

2、onic)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 2.08 mg/mL (3.85 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.08 mg/mL (3.85 mM); Clear solution1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEBIOLOGICAL ACTIVITY物活性 LY2562175種有效且有選擇性的 FXR 激動(dòng)劑，其 EC50 值為 193 nM。IC50 & Ta

3、rget EC50: 193 nM (FXR)體外研究 LY2562175 promotes transcriptional activation of human FXR in a cell-based co-transfection assay with anEC50 of 193 nM. LY2562175 promotes recruitment of a peptide from the nuclear receptor interaction domainof the coactivator SRC-1 with a relative EC50 of 121 nM and 93.5

4、% efficacy as compare to GW4064 1.體內(nèi)研究 LY2562175 causes a dose-dependent decrease in serum cholesterol and serum triglycerides. At a dose of10 mg/kg, the decrease in cholesterol with LY2562175 is 80% below vehicle-treated animals, and thedecrease in serum triglycerides is 76% from control group. The

5、 ED50 for serum cholesterol is determined tobe 2 and 3.4 mg/kg for serum triglycerides. Treatment of female ZDF rats with LY2562175 results in a dosedependent lowering of plasma triglycerides in the fasted and nonfasted states. When administered as a fixeddose combination with BRL49653, LY2562175 fu

6、rther lowers fasted and nonfasted plasma triglycerides.FPLC fractionation of the lipoproteins reveals that LY2562175 treatment results in a reduction in vLDL-C anda dramatic increase in HDL-c in this animal model 1.PROTOCOLKinase Assay 1 LY2562175 is tested in concentration-response curves by an FXR

7、-SRC-1 Cofactor Recruitment assay usingthe Alpha Screen technology according to the manufacturer instructions. Briefly, purified 6-HIS-taggedhuman FXR ligand-binding domain (amino acids 242-472), purified GST-tagged human SRC-1 nuclearreceptor-interacting domain (amino acids 220-394), Nickel Chelate

8、 donor beads and Anti-GST antibodyacceptor beads are mixed together and 12 L per well is aliquoted into 384 well plates. Add LY2562175 in 3L per well for a total assay volume of 15 L and incubate at room temperature in the dark for 4 hours. Afterincubation, LY2562175 that binds FXR and induces the i

9、nteraction between the FXR and SRC-1 will bringthe two bead types into proximity generating luminescence that is quantified using a Packard Fusioninstrument. Calculate EC50 values for LY2562175 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal To

10、 assess the potency and efficacy of LY2562175 in vivo, studies are conducted in 8 week old, male LDLRAdministration 1 null mice fed a “Western” diet. Animals are allowed to acclimate to the high fat/high cholesterol chowTD88137 (containing 0.15% cholesterol and 42% fat) for 2 weeks prior to the stud

11、y. Animals are divided intogroups of six and dosed once daily for 1 week by gavage with solutions of LY2562175 in situ sodium salt orwith vehicle (5% Solutol, 5% EtOH, 1 wt %/v CMC) at a dose volume of 5 mL/kg. On the seventh day,animals are bled by cardiac puncture under anesthesia with CO2. Serum

12、is prepared from individual animalsfor determination of cholesterol and triglycerides by enzymatic analysis. Pooled samples from each treatmentgroup are used for determination of lipoprotein subtypes. ED50 values (dose producing half-maximal effect)for the decrease in serum cholesterol and triglycer

13、ides are determined by nonlinear regression analysis 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemE1. Genin MJ, et al. Discovery of 6-(4-5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-ylmethoxypiperidin-1-yl)-1-methyl-1H-indole-3-carboxylic Acid: A Novel FXR Agonist for the Treatment of Dyslipidemia. J Med Chem. 2015 Dec 24;58(24):9768-72