IC50: < 5 nM
KT182 is an ABHD6 inhibitor.
α/β-Hydrolase domain containing 6 (ABHD6), a transmembrane serine hydrolase, hydrolyzes the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) to regulate certain forms of cannabinoid receptor-dependent signaling in the nervous system.
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].
Clinical trial: Up to now, KT182 is still in the preclinical development stage.
Reference:
[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.