title: 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.
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).
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Andreas
authors: A
authors: Gollner
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Dorothea
authors: D
authors: Rudolph
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Heribert
authors: H
authors: Arnhof
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Markus
authors: M
authors: Bauer
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Sophia M
authors: SM
authors: Blake
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Guido
authors: G
authors: Boehmelt
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Xiao-Ling
authors: XL
authors: Cockroft
authors: Boehringer Ingelheim Pharma GmbH & Co. KG , 88400 Biberach, Germany.
authors: Georg
authors: G
authors: Dahmann
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Peter
authors: P
authors: Ettmayer
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Thomas
authors: T
authors: Gerstberger
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Jale
authors: J
authors: Karolyi-Oezguer
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Dirk
authors: D
authors: Kessler
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Christiane
authors: C
authors: Kofink
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Juergen
authors: J
authors: Ramharter
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Jörg
authors: J
authors: Rinnenthal
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Alexander
authors: A
authors: Savchenko
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Renate
authors: R
authors: Schnitzer
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Harald
authors: H
authors: Weinstabl
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Ulrike
authors: U
authors: Weyer-Czernilofsky
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Tobias
authors: T
authors: Wunberg
authors: Boehringer Ingelheim RCV GmbH & Co. KG , Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
authors: Darryl B
authors: DB
authors: McConnell
mesh_terms: D000284:Administration, Oral; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007211:Indoles; D011760:Pyrrolidinones; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C000620074:spiro(3H-indole-3,2'-pyrrolidin)-2(1H)-one; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2