Abstract
The design, synthesis, evaluation, and identification of a novel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of human epidermal growth factor receptor-2 (HER-2) sheddase is described. Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decrease tumor size, cleaved HER-2 extracellular domain plasma levels, and potentiate the effects of the humanized anti-HER-2 monoclonal antibody (trastuzumab) in vivo in a HER-2 overexpressing cancer murine xenograft model.
MeSH terms
-
Administration, Oral
-
Amides / chemical synthesis*
-
Amides / pharmacokinetics
-
Amides / pharmacology
-
Animals
-
Antibodies, Monoclonal / pharmacology
-
Antibodies, Monoclonal, Humanized
-
Antineoplastic Agents / chemical synthesis*
-
Antineoplastic Agents / pharmacokinetics
-
Antineoplastic Agents / pharmacology
-
Cell Line, Tumor
-
Drug Screening Assays, Antitumor
-
Drug Synergism
-
Humans
-
Hydroxamic Acids / chemical synthesis*
-
Hydroxamic Acids / pharmacokinetics
-
Hydroxamic Acids / pharmacology
-
Mice
-
Molecular Conformation
-
Piperidines / chemical synthesis*
-
Piperidines / chemistry
-
Piperidines / pharmacology
-
Receptor, ErbB-2 / antagonists & inhibitors*
-
Spiro Compounds / chemical synthesis*
-
Spiro Compounds / chemistry
-
Spiro Compounds / pharmacology
-
Stereoisomerism
-
Structure-Activity Relationship
-
Transplantation, Heterologous
-
Trastuzumab
Substances
-
Amides
-
Antibodies, Monoclonal
-
Antibodies, Monoclonal, Humanized
-
Antineoplastic Agents
-
Hydroxamic Acids
-
INCB3619
-
Piperidines
-
Spiro Compounds
-
Receptor, ErbB-2
-
Trastuzumab