Journal of Medicinal Chemistry p. 10147 - 10162 (2016)
Update date:2022-08-03
Topics:
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, J?rg
Savchenko, Alexander
Schnitzer, Renate
Weinstabl, Harald
Weyer-Czernilofsky, Ulrike
Wunberg, Tobias
McConnell, Darryl B.
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).
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