Moreira VM

References (2)

Title : Probing the Interactions of Thiazole Abietane Inhibitors with the Human Serine Hydrolases ABHD16A and ABHD12 - Ahonen_2023_ACS.Med.Chem.Lett_14_1404
Author(s) : Ahonen TJ , Ng CP , Farinha B , Almeida B , Victor BL , Reynolds C , Kalso E , Yli-Kauhaluoma J , Greaves J , Moreira VM
Ref : ACS Med Chem Lett , 14 :1404 , 2023
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 microM (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.
ESTHER : Ahonen_2023_ACS.Med.Chem.Lett_14_1404
PubMedSearch : Ahonen_2023_ACS.Med.Chem.Lett_14_1404
PubMedID: 37849541
Gene_locus related to this paper: human-ABHD12 , human-ABHD16A

Title : Discovery of 12-Thiazole Abietanes as Selective Inhibitors of the Human Metabolic Serine Hydrolase hABHD16A - Ahonen_2018_ACS.Med.Chem.Lett_9_1269
Author(s) : Ahonen TJ , Savinainen JR , Yli-Kauhaluoma J , Kalso E , Laitinen JT , Moreira VM
Ref : ACS Med Chem Lett , 9 :1269 , 2018
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 muM 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.
ESTHER : Ahonen_2018_ACS.Med.Chem.Lett_9_1269
PubMedSearch : Ahonen_2018_ACS.Med.Chem.Lett_9_1269
PubMedID: 30613338
Gene_locus related to this paper: human-ABHD16A