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Bioorg Med Chem Lett. 2022 Apr 1;61:128625. doi: 10.1016/j.bmcl.2022.128625. Epub 2022 Feb 11.
The discovery of potent, bioavailable small molecule inhibitors of p53-HDM2 PPI led us to investigate subsequent modifications to address a CYP3A4 time-dependent inhibition liability. On the basis of the crystal structure of HDM2 in complex with 2, further functionalization of the solvent exposed area of the molecule that binds to Phe19 pocket were investigated as a strategy to modulate the molecule liphophilicity. Introduction of 2-oxo-nicotinic amide at Phe19 proved a viable strategy in obtaining inhibitors exempt from CYP3A4 time-dependent inhibition liability.
强效、生物可利用的小分子 p53-HDM2 PPI 抑制剂的发现促使我们研究后续修饰以解决 CYP3A4 时间依赖性抑制的问题。基于 HDM2 与 2 复合物的晶体结构，进一步研究了与 Phe19 口袋结合的分子溶剂暴露区域的功能化，以调节分子的亲脂性。在 Phe19 处引入 2-氧代烟酰胺被证明是获得免于 CYP3A4 时间依赖性抑制的抑制剂的可行策略。
