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)
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Abstract
α/β-Hydrolase
domain containing 6 (ABHD6) is a transmembrane
serine hydrolase that hydrolyzes the endogenous cannabinoid 2-arachidonoylglycerol
(2-AG) to regulate certain forms of cannabinoid receptor-dependent
signaling in the nervous system. The full spectrum of ABHD6 metabolic
activities and functions is currently unknown and would benefit from
selective, in vivo-active inhibitors. Here, we report the development
and characterization of an advanced series of irreversible (2-substituted)-piperidyl-1,2,3-triazole
urea inhibitors of ABHD6, including compounds KT182 and KT203, which
show exceptional potency and selectivity in cells (<5 nM) and,
at equivalent doses in mice (1 mg kg<sup>–1</sup>), act as
systemic and peripherally restricted ABHD6 inhibitors, respectively.
We also describe an orally bioavailable ABHD6 inhibitor, KT185, that
displays excellent selectivity against other brain and liver serine
hydrolases in vivo. We thus describe several chemical probes for biological
studies of ABHD6, including brain-penetrant and peripherally restricted
inhibitors that should prove of value for interrogating ABHD6 function
in animal models