Discovery of S-217622, a Noncovalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19
Tachibana* et al J. Med. Chem. 2022, 65, 9, 6499–6512
Naturally we would be drawn to a SARS-CoV2 Protease inhibitor paper. This one has been made openly available, which is a bonus. The team started with available chemical information from a few known inhibitors of the main protease of the virus. A virtual screen produced a subset of molecules to test, and this yielded a very good hit molecule that was none peptidic and non covalent binding. The compound had good in-vitro stability – kind of the hit we all wish we had. The paper descibes the three changes made to the side chains to yield optimal groups, but does lack the complete SAR picture of all of the iterations, which is a shame. The optimisation of the trifluoro benzen groups appears very similar to that of Sitagliptin. There is a good example of a triazole replacement for an amide too. Further in-vivo anti-viral data is presented.
In the same addition of J. Med. Chem is another paper made openly available. This has more complete SAR tables for your enjoyment.
Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor
Cano* et al J. Med. Chem. 2022, 65, 9, 6513–6540