Discovery of dihydrooxazolo[2,3-a]isoquinoliniums as highly specific inhibitors of hCE2

Human carboxylesterase 2 (hCE2) is one of the most abundant esterases distributed in human small intestine and colon, which participates in the hydrolysis of a variety of ester-bearing drugs and thereby affects the efficacy of these drugs. Herein, a new compound (23o) with a novel skeleton of dihydrooxazolo[2,3-a]isoquinolinium has been discovered with strong inhibition on hCE2 (IC50 = 1.19 mu M, K-i = 0.84 mu M) and more than 83.89 fold selectivity over hCE1 (IC50 > 100 mu M). Furthermore, 23o can inhibit hCE2 activity in living HepG2 cells with the IC50 value of 2.29 mu M, indicating that this compound has remarkable cell-membrane permeability and is capable for inhibiting intracellular hCE2. The SAR (structure-activity relationship) analysis and molecular docking results demonstrate that the novel skeleton of oxazolinium is essential for hCEs inhibitory activity and the benzyloxy moiety mainly contributes to the selectivity of hCE2 over hCE1.