Description
KT182 is a potent inhibitor of α/β-hydrolase domain-containing protein 6 (ABHD6) with IC
50 values of 1.7, 15.1, and 0.24 nM using Neuro2a membrane proteomes, recombinant ABHD6 in HEK293T cells, and Neuro2a cells
in situ, respectively. Following administration of KT182 (1 mg/kg, i.p.) in mice, ABHD6 is inactivated in liver and brain extracts, suggesting that it is brain-penetrant, unlike the closely related compound KT203 .
in vitro
the in-vitro potencies were tested for kt182 and the results found that kt182 could potently inhibit abhd6 as measured by gelbased competitive abpp and 2-ag hydrolysis assays. moreover, the in-situ potencies were measured by treating neuro2a cells with varying concentrations of kt182 for 4 h, and it was found that kt182 could inhibit abhd6 with ic50 values in the subnanomolar range [1].
in vivo
in animal study, mice were treated intraperitoneally with kt182 at various doses (0.1-1 mg/kg) for 4 h, and the results found that kt182 could produce near-complete blockade of abhd6 in the liver at the highest dose tested. moreover, kt182 at lower doses maintained around 80% inhibition of abhd6 in the liver and kt182 at higher doses showed impressive selectivity in the mouse liver, exhibiting little cross-reactivity against the numerous carboxylesterase enzymes. in addition, kt182 could also completely inactivate abhd6 in the mouse brain at 1 mg/kg [1].
References
[1] hsu kl, tsuboi k, chang jw, whitby lr, speers ae, pugh h, cravatt bf. discovery and optimization of piperidyl-1,2,3-triazole ureas as potent, selective, and in vivo-active inhibitors of α/β-hydrolase domain containing 6 (abhd6). j med chem. 2013 nov 14;56(21):8270-9.