Bayer Advances Clinical-Stage IRAK4 Inhibitors Zabedosertib (BAY1834845) and BAY1830839 for Immune-Inflammatory Diseases
Bayer
Pharmaceutical Product R&D Developer
Interleukin-1Receptor-Associated Kinase4（IRAK4) is a widely expressed protein, inTLR/IL-1RPlays a key role in signal transduction. WhenTLRs(ExceptTLR3) After identifying its corresponding ligand, it will recruitMyD88, and subsequently activateIRAK4。 Thereafter, further activationNF-κBPathway orMAPKPathway. Finally,MyD88-IRAK4Pathway activation promotes other processes associated with inflammation and inflammatory pain, including various inflammatory signaling molecules and enzymes (cytokines, chemokines, and cyclooxygenases).-2 [COX-2]) increased expression, and a variety of inflammation-related genesmRNAEnhanced stability. In summary,IRAK4The activation of the pathway is associated with inflammation and autoimmune diseases, such as atopic dermatitis, systemic lupus erythematosus, hidradenitis suppurativa, and rheumatoid arthritis. Therefore, modulationIRAK4Activity for the treatment of various immune-Inflammatory diseases offer an attractive therapeutic option.
Currently, some representative ones have entered the clinical stage.IRAK4Inhibitors/Degraders as shown in the figure below, some clinical trials have been terminated.
BayerThrough high-throughput screeningProprietary300Wanhua UnitedMaterial Library, find compounds5. The compound is stable in hepatocytes (rat), and in10 μMNo significant effect was shown at the concentration.CYP3A4、CYP1A2、CYP2C8、CYP2C9OrCYP2D6The inhibition. However, it is inCaco-2Exhibited strong efflux characteristics in the experiment.
Co-crystal structure of molecule 5 PDB 8BR7
Researchers designed and screened a set of molecules based on the docking molecular binding mode 5 (the co-crystal structure should not have been resolved at that time), resulting in the compound.6, nitrobenzene replaced with trifluoromethylpyridine, its activity and5Equivalent and improved membrane permeability.
Next, the researchers studied the indazole ring6Position (table2Substituents inR1) The potential impact on metabolism and activity. Introducing a methyl group, fluorine atom, or chlorine atom increases activity (table2; Compound7−9). The use of alkoxy groups further increased activity to single-digit nanomolar levels (table2; Compound10And11). The introduction of alkoxy groups not only controls the conformation but also occupies a certain amount of space, significantly enhancing activity.
At the same time, in order to reduce the impact of molecular weight on indazole2The position substitution was further optimized to obtain the compound.30, and for30Further optimization yielded two clinical compounds.BAY1834845 (Zabedosertib) And BAY1830839。
BAY1834845 docking mode in 8BR6
InKINOMEscanIn China,BAY1830839AndBAY1834845Showing good selectivity.
TREEspot for BAY1834845 at 0.1 μM (left) and 1 μM (right)
BAY1830839AndBAY1834845Stable in vitro metabolism, such as in hepatocyte assays from humans, primates, rats, and dogs, BAY1834845Show more thanBAY1830839Slightly higher stability (table11). In addition, inCaco-2In the cell assay data, both compounds exhibited high permeability (table12). Pharmacokinetics of the Two Compounds(PK)In China, after intravenous administration in rats and dogs,BAY1830839Displaylow-to-moderate CLblood；moderate-to-high Vss；intermediate-to-long t1/2; and high oral bioavailability (table13). In contrast,BAY1834845Demonstrate overall lower clearance and excellent oral bioavailability. Both have entered clinical trials, awaiting further updates.
https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c01714
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