Ahonen Tiina J, Ng Choa P, Farinha Beatriz, Almeida Bárbara, Victor Bruno L, Reynolds Christopher, Kalso Eija, Yli-Kauhaluoma Jari, Greaves Jennifer, Moreira Vânia M
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland.
Research Centre for Health and Life Sciences, Coventry University, CV1 5RW Coventry, U.K.
ACS Med Chem Lett. 2023 Sep 18;14(10):1404-1410. doi: 10.1021/acsmedchemlett.3c00313. eCollection 2023 Oct 12.
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 being the most effective, at 100 μM (55.1 ± 8.7%; < 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 . 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.
12-噻唑枞酸型二萜是hABHD16A的高选择性可逆抑制剂，可能减轻神经炎症。在本研究中，我们运用合成化学、基于活性的竞争性蛋白质分析以及计算方法，试图确定这类化合物对ABHD16A的抑制活性及对ABHD12选择性的相关结构决定因素。五种化合物显著抑制hABHD16A，同时能非常有效地区分对hABHD16A和hABHD12的抑制作用，其中化合物在100 μM时最为有效（55.1 ± 8.7%；P < 0.0001）。然而，如化合物所示，如果噻唑环的C2'位带有1-羟乙基，在存在A环酯的情况下，观察到对ABHD12的选择性出现显著转变。尽管我们的数据对于观察到的酶抑制是否为别构抑制尚无定论，但我们预计本文所呈现的构效关系将为该领域未来的药物发现工作提供启发。
