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

  • J Med Chem. 2016 Nov 23;59(22):10147-10162. doi: 10.1021/acs.jmedchem.6b00900.
Andreas Gollner  1 ,  Dorothea Rudolph  1 ,  Heribert Arnhof  1 ,  Markus Bauer  1 ,  Sophia M Blake  1 ,  Guido Boehmelt  1 ,  Xiao-Ling Cockroft  1 ,  Georg Dahmann  2 ,  Peter Ettmayer  1 ,  Thomas Gerstberger  1 ,  Jale Karolyi-Oezguer  1 ,  Dirk Kessler  1 ,  Christiane Kofink  1 ,  Juergen Ramharter  1 ,  Jörg Rinnenthal  1 ,  Alexander Savchenko  1 ,  Renate Schnitzer  1 ,  Harald Weinstabl  1 ,  Ulrike Weyer-Czernilofsky  1 ,  Tobias Wunberg  1 ,  Darryl B McConnell  1
Affiliations
  • 1. Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
  • 2. Boehringer Ingelheim Pharma GmbH & Co. KG , 88400 Biberach, Germany.
PMID: 27775892 DOI: 10.1021/acs.jmedchem.6b00900
Abstract

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).

Products