A Comprehensive Overview of Globally Approved JAK Inhibitors.

Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.

Discovery of novel oxazole-based macrocycles as anti-coronaviral agents targeting SARS-CoV-2 main protease.

We have discovered a family of synthetic oxazole-based macrocycles to be active against SARS-CoV-2. The synthesis, pharmacological properties, and docking studies of the compounds are reported in this study. The structure of the new macrocycles was confirmed by NMR spectroscopy and mass spectrometry. Compounds 13, 14, and 15a-c were evaluated for their anti-SARS-CoV-2 activity on SARS-COV-2 (NRC-03-nhCoV) virus in Vero-E6 cells. Isopropyl triester 13 and triacid 14 demonstrated superior inhibitory activities against SARS-CoV-2 compared to carboxamides 15a-c. MTT cytotoxicity assays showed that the CC50 (50% cytotoxicity concentration) of 13, 14, and 15a-c ranged from 159.1 to 741.8 µM and their safety indices ranged from 2.50 to 39.1. Study of the viral inhibition via different mechanisms of action (viral adsorption, replication, or virucidal property) showed that 14 had mild virucidal (60%) and inhibitory effects on virus adsorption (66%) at 20 µM concentrations. Compound 13 displayed several inhibitory effects at three levels, but the potency of its action is primarily virucidal. The inhibitory activity of compounds 13, 14, and 15a-c against the enzyme SARS-CoV-2 Mpro was evaluated. Isopropyl triester 13 had a significant inhibition activity against SARS-CoV-2 Mpro with an IC50 of 2.58 µM. Large substituents on the macrocyclic template significantly reduced the inhibitory effects of the compounds. Study of the docking of the compounds in the SARS CoV-2-Mpro active site showed that the most potent macrocycles 13 and 14 exhibited the best fit and highest affinity for the active site binding pocket. Taken together, the present study shows that the new macrocyclic compounds constitute a new family of SARS CoV-2-Mpro inhibitors that are worth being further optimized and developed.