GSK2256294A

Details:

The sEH inhibition by GSK2256294A exhibits good tolerability with rapid and sustained target inhibition. It displays favorable physicochemical properties, including good solubility in biorelevant media, particularly at lower pH values, and excellent preclinical pharmacokinetic characteristics with high oral bioavailability. GSK2256294A is a suitable drug for assessing the role of sEH in clinical studies, especially in diseases characterized by endothelial dysfunction or tissue repair abnormalities, such as diabetes, chronic obstructive pulmonary disease, and cardiovascular diseases.
GSK2256294A demonstrates potent cell-based activity, showing concentration-dependent inhibition of 14,15-EET conversion to 14,15-DHET in human, rat, and mouse whole blood in vitro, and a dose-dependent increase in the ratio of LTX/LTX diol in rat plasma after oral administration. GSK2256294A has been shown to alleviate smoke-induced inflammation in mice.
Inflammatory bowel disease (IBD) potentially benefits from the inhibition of sEH by GSK2256294A. IBD, such as ulcerative colitis (UC) and Crohn's disease (CD), is an immune-mediated chronic condition. Experimental evidence suggests that GSK2256294A can reduce the production of interleukin (IL)2, IL12p70, IL10, and TNFα in ex vivo cultures derived from ulcerative colitis and Crohn's disease patients. GSK2256294A reduces IL4 and IFNγ in ulcerative colitis, particularly IL1β in Crohn's disease.
In a short-term (10 days) mouse model of smoke-induced inflammation, acute administration of GSK1910364A, whether prophylactic or therapeutic, can mitigate inflammation by inhibiting its occurrence and promoting resolution. GSK1910364A, as an sEH inhibitor, exhibits potency, selectivity, efficacy in a mouse smoke-induced model, and acceptable preclinical safety.