Protease inhibitors, and preparation method and use thereof
A technology of medicinal salts and compounds, applied in the field of protease inhibitors, their preparation and application, capable of solving weak activity and other problems
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Embodiment 1
[0327] The screening of embodiment 1.3CLpro inhibitor
[0328] A series of non-covalent binders of 3CLpro of SARS-CoV-2 were identified by affinity screening and then scored by docking them into the substrate-binding pocket of 3CLpro; these molecules ranked highly in molecular docking studies were synthesized Three of the ( Figure 1A ).
Embodiment 2
[0329] Example 2. Synthesis of Exemplary Compounds
[0330] Compounds of the disclosure can be prepared according to standard chemical practice or as described herein, including the following synthetic schemes and in the preparation of , IIIb-2, IIIc, IVa or IVb-2 compounds, compounds 1 to 23, tautomers thereof, deuterated derivatives of said compounds or said tautomers, or the aforementioned pharmaceutically acceptable A description of the salt compound.
[0331] general plan
[0332] Compounds of Formula I can be prepared using the exemplary synthetic methods described in General Schemes A to D below. Variables not specifically defined in general schemes A to D, such as R 1 , R 2 , R 3 , V 1 , V 2 , V 3 , V 4 , W 1 , W 2 , W 3 , W 4 , m, n and o are as defined in formula I in this disclosure.
[0333] General plan A
[0334]
[0335] General Plan B
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[0337] General Plan C
[0338]
[0339] General Plan D
[0340]
[0341]Reagents and co...
Embodiment 3
[0402] Example 3. In vitro enzyme assay results
[0403] Using a fluorescence resonance energy transfer (FRET)-based sequential kinetic assay, tested Figure 1A The ability of the three compounds to inhibit 3CLpro. The fluorescent peptide Dabcyl-KTSAVLQ↓SGFRKM-E (Edans) (SEQ ID NO: 4) was used as a substrate for purified 3CLpro. After cleavage by 3CLpro, the fragment SGFRKM-E (Edans) (SEQ ID NO: 5) is released, and its fluorescence can be detected with excitation and emission wavelengths of 355 nm and 538 nm, respectively.
[0404] The final concentrations of 3CLpro and fluorescent substrate (Dabcyl-KTSAVLQ↓SGFRK M-E (Edans) (SEQ ID NO:4) were 100 nM and 100 μM, respectively. Briefly, 15 μL was dissolved in assay buffer (20 mM HEPES 7.4, 150 mM NaCl, Recombinant 3CLpro (0.4 μM) in 0.01% Triton X-100, 1 mM DTT) was incubated with a serial dilution of 1.5 μL of each compound for 1 hour at room temperature. At 30° C., a 384-well plate (Corning, CLS3575) Preheat for 5 min, then,...
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