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

Autor:	Ahonen TJ; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland., Ng CP; Research Centre for Health and Life Sciences, Coventry University, CV1 5RW Coventry, U.K., Farinha B; BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisboa, Portugal., Almeida B; BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisboa, Portugal., Victor BL; BioISI-Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisboa, Portugal., Reynolds C; Research Centre for Health and Life Sciences, Coventry University, CV1 5RW Coventry, U.K.; School of Life Sciences, University of Essex, CO4 3SQ Colchester, U.K., Kalso E; Department of Pharmacology, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland.; Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki University Hospital and University of Helsinki, FI-00029 Helsinki, Finland., Yli-Kauhaluoma J; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland., Greaves J; Research Centre for Health and Life Sciences, Coventry University, CV1 5RW Coventry, U.K., Moreira VM; Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland.; Centre for Neuroscience and Cell Biology, and Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3000-548 Coimbra, Portugal.; Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2023 Sep 18; Vol. 14 (10), pp. 1404-1410. Date of Electronic Publication: 2023 Sep 18 (Print Publication: 2023).
DOI:	10.1021/acsmedchemlett.3c00313
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest. (© 2023 The Authors. Published by American Chemical Society.)
Databáze:	MEDLINE
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