Download MendeleyA potent seven-membered cyclic BTK (Bruton's tyrosine Kinase) chiral inhibitor conceived by structure-based drug design to lock its bioactive conformation.
Lopez-Tapia, F., Lou, Y., Brotherton-Pleiss, C., Kuglstatter, A., So, S.S., Kondru, R.(2019) Bioorg Med Chem Lett 29: 1074-1078
- PubMed: 30857747
- DOI: https://doi.org/10.1016/j.bmcl.2019.03.001
- Primary Citation of Related Structures:
6HRP, 6HRT - PubMed Abstract:
A seven-membered cyclic chiral analog of potent lead BTK inhibitor 1 was envisioned by structure-based design to lock the molecule into its bioactive conformation. For the elaboration of the seven-membered ring, compound 1 pyridone 6-position was substituted with the purpose to prevent formation of reactive metabolites. Eventually, the cyclic chiral compound 3 maintained the high potency of 1, and most importantly showed no activity at either GSH or TDI assays suggesting no formation of reactive metabolites. The anticipated bound conformation of 3 to BTK was confirmed by X-ray crystallography. Synthetically, the crucial seven-membered ring formation was obtained by using TosMIC as a connective reagent.
Organizational Affiliation:
Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley 07110, United States. Electronic address: ftapia@cc.hawaii.edu.
