Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley 07110, United States.
Hoffmann-La Roche Ltd., pRED, Pharma Research & Early Development, 340 Kingsland Street, Nutley 07110, United States.
Bioorg Med Chem Lett. 2019 May 1;29(9):1074-1078. doi: 10.1016/j.bmcl.2019.03.001. Epub 2019 Mar 6.
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.
通过基于结构的设计，设想了一种七元环状手性类似物，以将潜在的 BTK 抑制剂 1 锁定在其生物活性构象中。为了构建七元环，将化合物 1 的吡啶酮 6-位取代，目的是防止形成反应性代谢物。最终，环状手性化合物 3 保持了 1 的高活性，并且最重要的是在 GSH 或 TDI 测定中均无活性，表明没有形成反应性代谢物。3 与 BTK 的预期结合构象通过 X 射线晶体学得到证实。在合成方面，使用 TosMIC 作为连接试剂获得了关键的七元环形成。
