Bispyrimidines as Potent Histamine H₄ Receptor Ligands: Delineation of Structure–Activity Relationships and Detailed H₄ Receptor Binding Mode

The basic methylpiperazine moiety is considered a necessary substructure for high histamine H₄ receptor (H₄R) affinity. This moiety is however also the metabolic hot spot for various classes of H₄R ligands (e.g., indolcarboxamides and pyrimidines). We set out to investigate whether mildly basic 2-aminopyrimidines in combination with the appropriate linker can serve as a replacement for the methylpiperazine moiety. In the series of 2-aminopyrimidines, the introduction of an additional 2-aminopyrimidine moiety in combination with the appropriate linker lead to bispyrimidines displaying p<i>K</i>_i values for binding the human H₄R up to 8.2. Furthermore, the methylpiperazine replacement results in compounds with improved metabolic properties. The attempt to transfer the knowledge generated in the class of bispyrimidines to the indolecarboxamides failed. Combining the derived structure–activity relationships with homology modeling leads to new detailed insights in the molecular aspects of ligand–H₄R binding in general and the binding mode of the described bispyrimidines in specific

Discovery of Novel Spiro[3<i>H</i>‑indole-3,2′-pyrrolidin]-2(1<i>H</i>)‑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[3<i>H</i>-indole-3,2′-pyrrolidin]-2­(1<i>H</i>)-one scaffold that are not prone to epimerization as observed for the initial spiro­[3<i>H</i>-indole-3,3′-pyrrolidin]-2­(1<i>H</i>)-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-[(3<i>S</i>,3′<i>S</i>,3′a<i>S</i>,5′<i>R</i>,6′a<i>S</i>)-6-chloro-3′-(3-chloro-2-fluorophenyl)-1′-(cyclopropylmethyl)-2-oxo-1,2,3′,3′a,4′,5′,6′,6′a-octahydro-1′<i>H</i>-spiro­[indole-3,2′-pyrrolo­[3,2-<i>b</i>]­pyrrole]-5′-yl]­benzoic acid (BI-0252)

Discovery of Novel Spiro[3<i>H</i>‑indole-3,2′-pyrrolidin]-2(1<i>H</i>)‑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[3<i>H</i>-indole-3,2′-pyrrolidin]-2­(1<i>H</i>)-one scaffold that are not prone to epimerization as observed for the initial spiro­[3<i>H</i>-indole-3,3′-pyrrolidin]-2­(1<i>H</i>)-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-[(3<i>S</i>,3′<i>S</i>,3′a<i>S</i>,5′<i>R</i>,6′a<i>S</i>)-6-chloro-3′-(3-chloro-2-fluorophenyl)-1′-(cyclopropylmethyl)-2-oxo-1,2,3′,3′a,4′,5′,6′,6′a-octahydro-1′<i>H</i>-spiro­[indole-3,2′-pyrrolo­[3,2-<i>b</i>]­pyrrole]-5′-yl]­benzoic acid (BI-0252)