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

Tiina J Ahonen; Juha R Savinainen; Jari Yli-Kauhaluoma; Eija Kalso; Jarmo T Laitinen; Vânia M Moreira

doi:10.1021/acsmedchemlett.8b00442

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

ACS Med Chem Lett. 2018 Nov 13;9(12):1269-1273. doi: 10.1021/acsmedchemlett.8b00442. eCollection 2018 Dec 13.

Authors

Tiina J Ahonen¹, Juha R Savinainen², Jari Yli-Kauhaluoma¹, Eija Kalso^{3

4}, Jarmo T Laitinen², Vânia M Moreira^{1

5}

Affiliations

¹ Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland.
² School of Medicine, Institute of Biomedicine, University of Eastern Finland, 80101 Kuopio, Finland.
³ Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.
⁴ Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki University Hospital and University of Helsinki, 00029 Helsinki, Finland.
⁵ Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, G4 0RE Glasgow, U.K.

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 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.