Discovery of 12-thiazole abietanes as selective inhibitors of the human metabolic serine hydrolase hABHD16A

Ahonen, Tiina J. and Savinainen, Juha R. and Yli-Kauhaluoma, Jari and Kalso, Eija and Laitinen, Jarmo T. and Moreira, Vânia M. (2018) Discovery of 12-thiazole abietanes as selective inhibitors of the human metabolic serine hydrolase hABHD16A. ACS Medicinal Chemistry Letters, 9 (12). pp. 1269-1273. ISSN 1948-5875

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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 2-methylthiazole derivative 18, with an IC50 value of 3.4 ± 0.2 µM and promising selectivity. ABHD16A has been highlighted as a new target for in-flammation-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 towards understanding the significance of hABHD16A inhibition in vivo.