ABSTRACT
Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Imidazoles/chemistry , Protein Kinase Inhibitors/chemistry , Pyrazines/chemistry , Agammaglobulinaemia Tyrosine Kinase/metabolism , Animals , Arthritis, Experimental/drug therapy , Binding Sites , Bridged Bicyclo Compounds/chemistry , Crystallography, X-Ray , Disease Models, Animal , Dogs , Dose-Response Relationship, Drug , Half-Life , Humans , Imidazoles/metabolism , Imidazoles/therapeutic use , Molecular Dynamics Simulation , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/therapeutic use , Pyrazines/metabolism , Pyrazines/therapeutic use , Rats , Rats, Wistar , Structure-Activity Relationship , src-Family Kinases/antagonists & inhibitors , src-Family Kinases/metabolismABSTRACT
The high frequency of activating RAS or BRAF mutations in cancer provides strong rationale for targeting the mitogen-activated protein kinase (MAPK) pathway. Selective BRAF and MAP-ERK kinase (MEK) inhibitors have shown clinical efficacy in patients with melanoma. However, the majority of responses are transient, and resistance is often associated with pathway reactivation of the extracellular signal-regulated kinase (ERK) signaling pathway. Here, we describe the identification and characterization of SCH772984, a novel and selective inhibitor of ERK1/2 that displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency in tumor cells with mutations in BRAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. Importantly, SCH772984 effectively inhibited MAPK signaling and cell proliferation in BRAF or MEK inhibitor-resistant models as well as in tumor cells resistant to concurrent treatment with BRAF and MEK inhibitors. These data support the clinical development of ERK inhibitors for tumors refractory to MAPK inhibitors.
Subject(s)
Extracellular Signal-Regulated MAP Kinases/genetics , MAP Kinase Kinase Kinases/genetics , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/genetics , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , MAP Kinase Kinase Kinases/antagonists & inhibitors , Mutation , Neoplasms/drug therapy , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Signal Transduction/drug effectsABSTRACT
Ozonolysis of 2-acetoxymethyl-1,5-anhydro-3,4,6-tri-O-benzyl-2-deoxy-D-arabino-hex-1-enitol gave 1-O-acetyl-3,4,6-tri-O-benzyl-4-O-formyl-D-arabino-hex-2-ulose (5). Subsequent hydrolysis and acetylation of 5 provided 1,2-di-O-acetyl-3,4,6-tri-O-benzyl-D-fructofuranose 6 in excellent yield. This methodology allows specific deuteration at C-1 of a protected D-fructofuranose derivative. This approach therefore could serve as [6+1-1] formulation for hexose series inter-conversion, that is, aldohexopyranose to ketohexofuranose.
