Discovery of Novel Spiro[3H‑indole-3,2′-pyrrolidin]-2(1H)‑one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2–p53 Interaction

Scaffold modification based on Wang’s pioneering MDM2–p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro­[3H-indole-3,2′-pyrrolidin]-2­(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro­[3H-indole-3,3′-pyrrolidin]-2­(1H)-one scaffold. Further structure-based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein–protein interaction (PPI) with TP53. The compounds are highly selective and show in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for 4-[(3S,3′S,3′aS,5′R,6′aS)-6-chloro-3′-(3-chloro-2-fluorophenyl)-1′-(cyclopropylmethyl)-2-oxo-1,2,3′,3′a,4′,5′,6′,6′a-octahydro-1′H-spiro­[indole-3,2′-pyrrolo­[3,2-b]­pyrrole]-5′-yl]­benzoic acid (BI-0252).

基于Wang所开创的MDM2-p53抑制剂进行骨架修饰，得到一类结构新颖、化学稳定性优异的螺环氧化吲哚类化合物（spiro-oxindole），其母核为螺[3H-吲哚-3,2′-吡咯烷]-2(1H)-酮（spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-one），与初始的螺[3H-吲哚-3,3′-吡咯烷]-2(1H)-酮（spiro[3H-indole-3,3′-pyrrolidin]-2(1H)-one）母核相比，这类化合物不易发生差向异构化。受天然产物结构骨架的启发，通过进一步基于结构的优化，得到了一套适配性极佳的复杂稠环体系，该体系可特异性结合MDM2蛋白并阻断其与TP53的蛋白质-蛋白质相互作用（PPI）。该类化合物具有极高的靶点选择性，即便采用单次给药方案，在SJSA-1异种移植模型中也展现出显著的体内药效，这一结论在化合物4-[(3S,3′S,3′aS,5′R,6′aS)-6-氯-3′-(3-氯-2-氟苯基)-1′-(环丙基甲基)-2-氧代-1,2,3′,3′a,4′,5′,6′,6′a-八氢-1′H-螺[吲哚-3,2′-吡咯并[3,2-b]吡咯]-5′-基]苯甲酸（BI-0252）的相关实验中得到了验证。