Discovery of 12-Thiazole Abietanes as Selective Inhibitors of the Human Metabolic Serine Hydrolase hABHD16A

Abstract

Screening of an in-house library of compounds identified 12-thiazole abietanes as a new class of reversible inhibitors of the human metabolic serine hydrolase. Further optimization of the first hit compound lead to the 2methylthiazole derivative 18, with an IC 50 value of 3.4 ± 0.2 μM and promising selectivity. ABHD16A has been highlighted as a new target for inflammation-mediated pain, although selective inhibitors of hABHD16A (human ABHD16A) have not yet been reported. Our study presents abietane-type diterpenoids as an attractive starting point for the design of selective ABHD16A inhibitors, which will contribute toward understanding the significance of hABHD16A inhibition in vivo.

30th Annual GP2A Medicinal Chemistry Conference

“…In the screening of an in-house library of compounds, we have identified 12-thiazole abietanes as a new class of reversible inhibitors of the human metabolic serine hydrolase [ 122 ]. Upon the optimization of the first hit compound we discovered a 2-methylthiazole derivative with an IC 50 value of 3.4 ± 0.2 µM and promising selectivity towards ABHD16A.…”

α/β-Hydrolase Domain (ABHD) Inhibitors as New Potential Therapeutic Options against Lipid-Related Diseases

“…The most recently discovered ABHD16A inhibitor is a diterpenoid of the abietane family, compound 66 (Figure ), which was selected as the most promising inhibitor from a screening of an in-house library of 50 similar derivatives . Compound 66 led to a 23% remaining activity of ABHD16A when tested in lysates of HEK293 cells transfected with ABHD16A (IC 50 value of 3.4 μM).…”

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

“…A look at how promiscuous 28 binds on the AlphaFold models showed the thiazole ring positioned toward the catalytic Ser residue instead of the ester group on ring A, in both enzymes (Figure A,B). We should note that the ester group on ring A of the abietanes is exceptionally stable and only affected by harsh reactions conditions, such as strong base. ,− Whereas in ABHD12, the hydroxyl group of the thiazole ring of 28 is hydrogen bonded with the catalytic Ser residue (Figure A), in ABHD16A, the same group is hydrogen bonded to a carbonyl group belonging to Ile 417 (Figure B). Such differences do not translate in significant changes in the docking poses or in the calculated binding free energy, which is consistent with the fact that 28 inhibits both enzymes.…”

“…10 Finally, 12-thiazole abietanes were reported as reversible inhibitors of human ABHD16A (Figure 1, compounds 13 and 14), some with outstanding selectivity among a panel of other serine hydrolyses from rat cerebellar membrane proteome. 26 In this work, we set out to establish general chemical determinants of compound selectivity for ABHD16A over ABHD12, using 12-thiazole abietanes as a study model. Through synthetic chemistry, we designed novel compound sets to build robust structure−activity.…”

“…Potent ABHD16A inhibitors, with a certain degree of selectivity, include 1,3,4-oxadiazol-2­(3 H )-ones (e.g., 12 , Figure ) and α-alkylidene-β-lactone-based inhibitors (e.g., 11 , Figure ), yet were not suitable for in vivo studies . Finally, 12-thiazole abietanes were reported as reversible inhibitors of human ABHD16A (Figure , compounds 13 and 14 ), some with outstanding selectivity among a panel of other serine hydrolyses from rat cerebellar membrane proteome …”