Probing the Interactions of Thiazole Abietane Inhibitors with the Human Serine Hydrolases ABHD16A and ABHD12

Abstract

12-Thiazole abietanes are highly selective reversible inhibitors of hABHD16A that could potentially alleviate neuroinflammation. In this study, we used synthetic chemistry, competitive activity-based protein profiling, and computational methodologies to try to establish relevant structural determinants of activity and selectivity of this class of compounds for inhibiting ABHD16A over ABHD12. Five compounds significantly inhibited hABHD16A but also very efficiently discriminated between inhibition of hABHD16A and hABHD12, with compound 35 being the most effective, at 100 μM (55.1 ± 8.7%; p < 0.0001). However, an outstanding switch in the selectivity toward ABHD12 was observed in the presence of a ring A ester, if the C2′ position of the thiazole ring possessed a 1-hydroxyethyl group, as in compound 28. Although our data were inconclusive as to whether the observed enzyme inhibition is allosteric or not, we anticipate that the structure−activity relationships presented herein will inspire future drug discovery efforts in this field.

Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases

“…Both KC01 and KC02 are, however, not pharmacologically active in animal models. Another chemotype that has been reported to inhibit ABHD16A is the thiazole abietanes. , While these compounds show inhibition of ABHD16A in lysates, there are no reports available that describe their efficacy to inhibit ABHD16A in mammalian cellular systems or animal models. To the best of our knowledge, no selective in vivo active inhibitors are described for ABHD16A.…”