GW 4869 (hydrochloride hydrate)

GW 4869 (hydrochloride hydrate) is a noncompetitive inhibitor of neutral sphingomyelinase (N-SMase) with an IC50 of 1 μM [1].

N-SMase, one of sphingomyelinases, is involved in sphingomyelin (SM) hydrolysis which is one of two main routes for the generation of ceramide. The sphingolipid ceramide has been shown to induce programmed cell death [1].

GW 4869 was selective for N-SMase, and did not inhibit acid SMase (A-SMase) at up to at least 150 μM. In MCF7 cells, GW 4869 at 10 μM partially inhibited tumor necrosis factor (TNF)-induced SM hydrolysis, and 20 μM of the compound completely protected SM from hydrolysis. The addition of 10 ~ 20 μM GW 4869 completely inhibited the initial accumulation of ceramide, and this effect was only partially lost at later time points (24 h) [1].

In male C57BL/6J mice, GW 4869 (1.25 mg/kg, i.p., q.d., 7 days prior and during behavioral testing for a total of 21 daily injections) impaired early phases of spatial reference memory, but did not decrease latency to locate the hidden platform with repeated training trials [2].

References:

[1]. Luberto C, Hassler D F, Signorelli P, et al. Inhibition of tumor necrosis factor-induced cell death in MCF7 by a novel inhibitor of neutral sphingomyelinase. Journal of Biological Chemistry, 2002, 277(43): 41128-41139.

[2]. Tabatadze N, Savonenko A, Song H, et al. Inhibition of neutral sphingomyelinase-2 perturbs brain sphingolipid balance and spatial memory in mice. Journal of Neuroscience Research, 2010, 88(13): 2940-2951.