BMS 833923 Chemical Properties

Density 

1.252±0.06 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

≥47.4 mg/mL in DMSO; insoluble in H2O; ≥5.14 mg/mL in EtOH with gentle warming and ultrasonic

form 

solid

pka

13.42±0.70(Predicted)

color 

Light yellow to yellow

InChIKey

KLRRGBHZCJLIEL-UHFFFAOYSA-N

SMILES

C(NC1=CC(CNC)=CC=C1C)(=O)C1=CC=C(NC2=NC(C3=CC=CC=C3)=C3C(=N2)C=CC=C3)C=C1

BMS 833923 Usage And Synthesis

Description

Smoothened (Smo) is a cell surface receptor that, with Patched, mediates sonic hedgehog (Shh) signaling to regulate gene expression through the Gli transcription factors. BMS 833923 is an orally bioavailable inhibitor of Smo. It blocks binding of BODIPY cyclopamine (IC₅₀ = 21 nM) and inhibits Gli activation in cell lines that express wild-type Smo or activated mutant forms of Smo (IC₅₀s = 6-35 nM). BMS 833923 robustly inhibits Shh pathway activity and prevents tumor growth in medulloblastoma and pancreatic carcinoma xenograft models.

Uses

BMS 833923 is an antagonist of smoothened, a key hedgehog (Hh) pathway regulator.

Synthesis

GENERAL STEPS: To a stirred suspension of 4-(4-phenylquinazolin-2-ylamino)benzoic acid (1.19 g, 3.49 mmol) prepared as described in Example 10 in dichloromethane (50 mL) was added catalytic amounts of dimethylformamide (100 μL) and thionyl chloride (1.50 mL, 20.6 mmol), and the resulting mixture was stirred at room temperature overnight. The solid was filtered, washed with hexane and dried under reduced pressure (high vacuum) to afford 4-(4-phenylquinazolin-2-ylamino)benzoyl chloride as a yellow solid (1.21 g, 97%). This was then added batchwise to a solution of commercially available 3-amino-4-methylbenzenemethanol (600 mg, 4.37 mmol) and triethylamine (1.0 mL, 7.2 mmol) in dichloromethane (50 mL), which had been cooled to 0 °C. The mixture was then cooled to 0 °C and the solution was mixed to a temperature of 0 °C. The mixture was warmed to room temperature overnight, then the solid was collected by filtration, washed with saturated sodium bicarbonate and water and dried under reduced pressure to afford N-(5-hydroxymethyl-2-methylphenyl)-4-(4-phenylquinazolin-2-ylamino)benzamide as a pure yellow solid (1.33 g, 86%). To a dichloromethane (50 mL) suspension of N-(5-hydroxymethyl-2-methylphenyl)-4-(4-phenylquinazolin-2-ylamino)benzamide (1.88 g, 4.08 mmol) which was cooled to 0 °C was slowly added thionyl chloride (475 μL, 6.54 mmol) and the mixture was stirred at 0 °C for 2 hours. Excess thionyl chloride and dichloromethane were removed on a rotary evaporator. The residue was stirred with ether, filtered, washed with ether and dried to give N-(5-chloromethyl-2-methylphenyl)-4-(4-phenylquinazolin-2-ylamino)benzamide as a yellow solid (2.15 g, 100%). This was then added to a tetrahydrofuran solution (20 mL, 32 mmol) of 1.6 M methylamine which was cooled to 0 °C in an ice bath. The stirred mixture was warmed to room temperature overnight and then concentrated on a rotary evaporator. The residue was redissolved in dichloromethane, washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent was then removed on a rotary evaporator and the residue was purified by fast column chromatography to afford N-(2-methyl-5-((methylamino)methyl)phenyl)-4-((4-phenylquinazolin-2- yl)amino)benzamide (1.12 g, 57%) as a yellow solid.1H NMR (400 MHz, DMSO-d6): δ 10.33 (s, 1H) 9.71 (s, 1H), 8.17 (d, 2H), 8.00 (d, 2H), 7.89-7.79 (m, 5H), 7.65 (m, 3H), 7.42 (m, 1H), 7.34 (s, 1H), 7.21 (d, 1H), 7.12 (d, 1H), 3.65 (s, 2H), 2.28 (s, 3H), 2.23 (s, 3H).MS (EI) for C30H27N5O: 474.2 (MH+).

in vivo

References

[1] Patent: WO2008/112913, 2008, A1. Location in patent: Page/Page column 174-175

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