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

• Published in: Journal of medicinal chemistry 2016-11, Vol.59 (22), p.10147-10162
• Main Authors: Gollner, Andreas, Rudolph, Dorothea, Arnhof, Heribert, Bauer, Markus, Blake, Sophia M, Boehmelt, Guido, Cockroft, Xiao-Ling, Dahmann, Georg, Ettmayer, Peter, Gerstberger, Thomas, Karolyi-Oezguer, Jale, Kessler, Dirk, Kofink, Christiane, Ramharter, Juergen, Rinnenthal, Jörg, Savchenko, Alexander, Schnitzer, Renate, Weinstabl, Harald, Weyer-Czernilofsky, Ulrike, Wunberg, Tobias, McConnell, Darryl B
• Format: Article
• Language: English
• Subjects: Administration, Oral; Dose-Response Relationship, Drug; Drug Discovery; Humans; Indoles - administration & dosage; Indoles - chemistry; Indoles - pharmacology; Models, Molecular; Molecular Structure; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - metabolism; Pyrrolidinones - administration & dosage; Pyrrolidinones - chemistry; Pyrrolidinones - pharmacology; Spiro Compounds - administration & dosage; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Structure-Activity Relationship; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00900

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).