Submission Details
Molecule(s):
Cc1cc(C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)C[C@H](/C=C/S(C)(=O)=O)C[C@@H]2CCNC2=O)C(C)C)no1
Design Rationale:
This was designed on the basis of the compound co-crystallized with Sars-CoV2 main protease, PDB reference 6LU7. The compound is not dissimilar to rupintrivir (AG7088) which reached phase II for rhinovirus. However, the replacement of the vinyl ester of rupintrivir with a vinyl sulfone should improve the PK and also increase the electrophilicity of the warhead. See Palmer et al., J. Med. Chem. 1995, 38, 3193-3196.
Other Notes:
Using a phenyl rather than methyl sulfone might increase the electrophilicity as well, consider a benzyl sulfone too as each should be accommodated (based on the benzyl ester of the compound co-crystallized in 6LU7. Consider also a 4-fluoroleucine at P2 as hydroxylation metabolism can often occur on the leucine methine, which can then cyclize onto the P2-P1 amide and spit out the warhead portion, which on its own will not be inhibitory. The 4-fluoroleucine synthesis is easy to accomplish thanks to Merck scientists during the preparation of odanacatib (see, for instance Gauthier et al, Bioorg Med Chem Lett., 2008, 18, 923-928.