Design, synthesis, and biological evaluation of substituted oxopyridine derivatives as selective FXIa inhibitors

Abstract

To explore selective FXIa inhibitors, a series of compounds was rationally designed using computer-aided drug design (CADD) and synthesized by introducing hydrophobic P1 fragments, which could strengthen the interaction with the S1 pocket of FXIa and weaken the interaction with plasma kallikrein. All the compounds were tested for the inhibition of FXIa, and some of them were further evaluated via plasma kallikrein selectivity and clotting assays. Compound 4c exhibited excellent in vitro potency, good membrane permeability and higher selectivity than asundexian. Furthermore, 4c showed an excellent pharmacokinetic property in rats after intravenous or oral administration. These results indicate that 4c can serve as a novel FXIa inhibitor that has potential clinical applications in patients.

Fig. 1. Chemical structures of the representative FXIa inhibitors: 1 (asundexian),2 (milvexian),3 (SHR2285),S-1, and S-2 (ref. 30).

Scheme 1. Reagents and conditions: (a) Pd(PPh₃)₄, K₂CO₃, 1,4-dioxane; (b) TMSN₃, tBuONO, CH₃CN; (c) CuSO₄, sodium ascorbate, THF/H₂O; (d) HBr·Py, DMF; (e) tetramethylguanidine, iPrOH/acetone.

Scheme 2. Reagents and conditions: (a) toluene; (b) NIS, CH₃CN; (c) HBr·Py, DMF; (d) tetramethylguanidine, iPrOH/acetone; (e) boronic acid pinacol esters, Pd(dppf)Cl₂, K₂CO₃, 1,4-dioxane; (f) piperazine-2,5-dione or 2-pyrrolidinone, CuI, K₃PO₄, N,N′-dimethyl-1,2-ethanediamine, DMF.

Fig. 2. Hydrophobicity surface model created using ChimeraX (the default coloring is from dark cyan for most hydrophilic through white to dark golden for hydrophobic. Asundexian is shown as sticks within the surface model).

Fig. 3. Design strategy for the target compounds.

Fig. 4. Mean concentration of 4c in the plasma of rats after oral/intravenous administration (n = 3).

Fig. 5. Ligand–protein contacts obtained by the last 20 ns trajectories.