ABSTRACT
N-Substituted azaindoles have been discovered as pan-PIM kinase inhibitors. Initial SAR, early ADME and PK/PD data of a series of compounds is described and led to the identification of promising pan-PIM inhibitors which validated our interest in the 7-azaindole scaffold and led us to pursue the identification of a clinical candidate.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/metabolism , Animals , Crystallography, X-Ray , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Half-Life , Humans , Indoles/metabolism , Inhibitory Concentration 50 , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Proto-Oncogene Proteins c-pim-1/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Novel N-substituted azaindoles have been discovered as PIM1 inhibitors. X-ray structures have played a significant role in orienting the chemistry effort in the initial phase of hit confirmation. Disclosure of an unconventional binding mode for 1 and 2, as demonstrated by X-ray crystallography, is presented and was an important factor in selecting and advancing a lead series.
Subject(s)
Indoles/chemistry , Indoles/pharmacology , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Humans , Indoles/metabolism , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-pim-1/metabolism , Structure-Activity RelationshipABSTRACT
A phenotypic screen (PS) is used to identify compounds causing a desired phenotype in a complex biological system where mechanisms and targets are largely unknown. Deconvoluting the mechanism of action of actives and identification of relevant targets and pathways remains a formidable challenge. Current methods fail to use the rich information available regarding compounds and their targets in a systematic way for this deconvolution. We have developed an enrichment analysis algorithm to identify targets associated with the desired phenotype in a rigorous data-driven manner using actives and hundreds of thousands of inactives in a PS, as well as results of thousands of available legacy target-based screens in an institution. Our method quantifies association between the PS and targets while reducing sampling bias, which leads to identification of novel targets, additional chemical matter, and appropriate assays. Its use is illustrated using two examples from our laboratories: TRAIL and DNA fragmentation. Enrichment analysis of these PSs is discussed using both biological pathway analysis and known cell biology to demonstrate the value of our method. We believe this enrichment analysis method is an indispensable tool for the analysis of PSs.
Subject(s)
Drug Evaluation, Preclinical/methods , Phenotype , Algorithms , DNA Fragmentation/drug effects , High-Throughput Screening Assays , TNF-Related Apoptosis-Inducing Ligand/metabolismABSTRACT
A series of tetrahydroisoquinolines were designed, synthesized and evaluated as the first non-natural product type of compounds with dual D(1) receptor (D(1)R) agonism and D(2) receptor (D(2)R) antagonism properties for treatment of schizophrenia. The initial SAR of the series was explored. The lead in the series, 3g, exhibited high affinity and good potency. Compound 3g displayed 95% of D(1)R occupancy (10 mg/kg, sc) and 75% of D(2)R occupancy (10 mg/kg, sc) in the striatum of male CD-1 mice. The series exhibited unique pharmacology and merit as tool compounds for target validation and future optimizations.
Subject(s)
Dopamine D2 Receptor Antagonists , Receptors, Dopamine D1/agonists , Schizophrenia/drug therapy , Tetrahydroisoquinolines/chemistry , Tetrahydroisoquinolines/pharmacology , Animals , Drug Design , Male , Mice , Receptors, Dopamine D1/metabolism , Receptors, Dopamine D2/metabolism , Schizophrenia/pathology , Structure-Activity Relationship , Tetrahydroisoquinolines/chemical synthesisABSTRACT
A new generation of PNP compounds bearing different diarylphosphine groups were prepared and used as ligands in palladium-catalysed Suzuki cross-coupling reactions. Rates of oxidative addition of iodobenzene to (PNP)Pd[0] complexes were measured using UV spectroscopy. Synergistic effects between the N- and P- substituents were identified and correlated in redox and catalytic chemistry.
ABSTRACT
The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.
