ABSTRACT
Abrogation of errant signaling along the MAPK pathway through the inhibition of B-RAF kinase is a validated approach for the treatment of pathway-dependent cancers. We report the development of imidazo-benzimidazoles as potent B-RAF inhibitors. Robust in vivo efficacy coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and PD-efficacy relationships led to the identification of RAF265, 1, which has advanced into clinical trials.
ABSTRACT
Two scaffolds based on 5,6-fused heterocyclic backbones were designed and synthesized as Raf kinase inhibitors. The scaffolds were assessed for in vitro pan-Raf inhibition, activity in cell proliferation and target modulation assays, and pharmacokinetic parameters.
Subject(s)
Amides/chemical synthesis , Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Heterocyclic Compounds/chemical synthesis , raf Kinases/antagonists & inhibitors , Amides/chemistry , Amides/pharmacology , Binding Sites , Cell Proliferation , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of arylaminobenzimidazoles was designed and synthesized as Raf kinase inhibitors. Exploration of the structure-activity relationship resulted in compounds that are potent in vitro and show desirable in vivo properties.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Drug Design , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , raf Kinases/antagonists & inhibitors , Administration, Oral , Animals , Benzimidazoles/administration & dosage , Benzimidazoles/chemistry , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Female , Humans , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Structure, Tertiary , Stereoisomerism , Structure-Activity Relationship , Xenograft Model Antitumor Assays , raf Kinases/metabolismABSTRACT
The previously unknown stereoisomers 3, 4, ent-1, and ent-4 of the tris(pyrrolidinoindoline) alkaloids hodgkinsine (1) and hodgkinsine B (2) were prepared by stereocontrolled total synthesis. In each synthesis, a catalyst-controlled intramolecular Heck reaction was the key step in appending a third cis-pyrrolidinoindoline ring to a hexacyclic chimonanthine precursor. Results of the preliminary evaluation of these hodgkinsine stereoisomers in the tail flick and capsaicin pain models are reported.
