Sb-742457 Chemical Properties

Boiling point:

608.3±45.0 °C(Predicted)

Density 

1.292

storage temp. 

Store at -20°C

solubility 

insoluble in H2O; ≥17.65 mg/mL in DMSO; ≥2.13 mg/mL in EtOH with gentle warming and ultrasonic

form 

solid

pka

8?+-.0.10(Predicted)

color 

Light yellow to yellow

InChI

InChI=1S/C19H19N3O2S/c23-25(24,16-6-2-1-3-7-16)17-13-15-5-4-8-18(19(15)21-14-17)22-11-9-20-10-12-22/h1-8,13-14,20H,9-12H2

InChIKey

JJZFWROHYSMCMU-UHFFFAOYSA-N

SMILES

N1C2C(=CC=CC=2N2CCNCC2)C=C(S(C2=CC=CC=C2)(=O)=O)C=1

Sb-742457 Usage And Synthesis

Description

SB-742457 is an orally bioavailable antagonist of the serotonin (5-HT) receptor subtype 5-HT₆ (K_i = 1.4 nM). SB-742457 (1 μM) also binds to 5-HT_1B, 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors with high affinity. SB-742457 reduces 5-HT₆ activation of G_s-mediated cAMP production in a concentration-dependent manner with an EC₅₀ value of 21 nM in NG108-15 neuroblastoma cells. In vivo, SB-742457 (1.5 mg/kg, p.o.) reverses deficits in novel object recognition induced by scopolamine in rats. It also reverses age-induced impairments in spatial memory acquisition and retention in rats in the Morris water maze. SB-742457 (3.0 mg/kg, i.p.) reduces the number of licking bouts by 24% compared with control in rats trained to lick a glucose solution, indicating a role in satiety and obesity management.

Uses

SB 742457 is a selective 5-HT6 receptor antagonist which is known to be involved in improving cognitive function.

Synthesis

To a 100 mL three-neck flask was added Pd2(dba)3 (174 mg, 0.19 mmol, 0.03 equiv), 8-iodo-3-benzenesulfonylquinoline (2.5 g, 6.33 mmol), 1,1'-bis(diphenylphosphino)ferrocene (316 mg, 0.57 mmol), sodium tert-butoxide (851 mg, 8.86 mmol, 1.4 equivalents) and piperazine (2.72 g, 31.6 mmol, 5 equivalents). The flask was evacuated and displaced 4 times with nitrogen, then anhydrous 1,4-dioxane (17.5 mL, 7 vol) was added. The mixture was stirred and heated to 40 °C for 16 hours of reaction. After completion of the reaction, the dark solution was cooled to room temperature, dichloromethane (12.5 mL) was added and washed with deionized water (12.5 mL). The aqueous phase was extracted with dichloromethane and the combined organic phases were extracted with 5 M HCl (2 x 12.5 mL). The combined aqueous phases were washed with dichloromethane (2.5 mL) and transferred to a conical flask, dichloromethane (12.5 mL) was added and the flask was cooled in an ice water bath. An aqueous 1 M sodium hydroxide solution (13 mL) was added with stirring and the mixture was then stirred at room temperature until all solids were dissolved. The lower organic phase was separated, the aqueous phase was extracted with dichloromethane (7.5 mL), and the combined organic phases were concentrated under reduced pressure to about 5 mL. Crystallization was induced by the addition of iso-octane (2.5 mL) to the dark brown solution, and the mixture was stirred at room temperature for 5 minutes, followed by the slow addition of iso-octane (22.5 mL) over a 5 minute period. The mixture was aged at room temperature for 1.5 hours, then cooled in an ice water bath for 30 minutes, filtered and the filter cake was washed with isooctane (5 mL). The filter cake was dried under reduced pressure to afford the target product 3-(phenylsulfonyl)-8-(piperazin-1-yl)quinoline (1.67 g, 75% yield).1H NMR (CDCl3) δ: 1.6 (1H, bs), 3.18 (4H, m), 3.34 (4H, m), 7.27 (1H, m), 7.49-7.60 (5H, m), 8.01 (2H, dd), 8.75 (1H, d), 9.21 (1H, d).

target

5-HT6

IC 50

5-HT₆ Receptor: 9.63 (pKi)

References

[1] aaron t. t. chuang, andrew foley, perdita l. pugh, david sunter, xin tong, ciaran regan, lee a. dawson, andrew d. medhurst, neil upton.5-ht6 receptor antagonist sb-742457 as a novel cognitive enhancing agent for alzheimer’s disease. alzheimer's & dementia: the journal of the alzheimer's association volume 2, issue 3, supplement, pages s631–s632, july 2006

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