ABSTRACT
Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo.
Subject(s)
Drug Design , Imidazoles/chemistry , Phosphodiesterase Inhibitors/chemistry , Phosphoric Diester Hydrolases/chemistry , Pyridines/chemistry , Animals , Binding Sites , Glucose Tolerance Test , Half-Life , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Insulin/metabolism , Molecular Docking Simulation , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphoric Diester Hydrolases/metabolism , Protein Binding , Protein Structure, Tertiary , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A series of piperidine carboxamides were developed as potent antagonists of the transient receptor potential vanilloid-1 (TRPV1), an emerging target for the treatment of pain. A focused library of polar head groups led to the identification of a benzoxazinone amide that afforded good potency in cell-based assays. Synthesis and a QSAR model will be presented.
Subject(s)
Amides/chemistry , Benzoxazines/pharmacology , Piperidines/chemistry , TRPV Cation Channels/antagonists & inhibitors , Benzoxazines/chemistry , Capsaicin/chemistry , Carrier Proteins/antagonists & inhibitors , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Models, Chemical , Molecular Conformation , Protein Binding , Quantitative Structure-Activity Relationship , Structure-Activity RelationshipABSTRACT
A novel microfluidics-based bilayer device with a discrete parenchymal chamber modeled upon hepatic organ architecture is described. The microfluidics network was designed using computational models to provide appropriate flow behavior based on physiological data from human microvasculature. Patterned silicon wafer molds were used to generate films with the vascular-based microfluidics network design and parenchymal chamber by soft lithography. The assembled device harbors hepatocytes behind a nanoporous membrane that permits transport of metabolites and small proteins while protecting them from the effects of shear stress. The device can sustain both human hepatoma cells and primary rat hepatocytes by continuous in vitro perfusion of medium, allowing proliferation and maintaining hepatic functions such as serum protein synthesis and metabolism. The design and fabrication processes are scalable, enabling the device concept to serve as both a platform technology for drug discovery and toxicity, and for the continuing development of an improved liver-assist device.
Subject(s)
Hepatocytes/cytology , Liver, Artificial , Membranes, Artificial , Microfluidic Analytical Techniques/instrumentation , Microfluidic Analytical Techniques/methods , Animals , Cell Culture Techniques/instrumentation , Cell Culture Techniques/methods , Cell Line, Tumor , Drug Evaluation, Preclinical/instrumentation , Drug Evaluation, Preclinical/methods , Humans , Male , Porosity , Rats , Rats, Inbred Lew , Silicon/chemistryABSTRACT
A series of 2'-aminoanilides have been identified which exhibit potent and selective inhibitory activity against the cFMS tyrosine kinase. Initial SAR studies within this series are described which examine aroyl and amino group substitutions, as well as the introduction of hydrophilic substituents on the benzene core. Compound 47 inhibits the isolated enzyme (IC(50)=0.027 microM) and blocks CSF-1-induced proliferation of bone marrow-derived macrophages (IC(50)=0.11 microM) and as such, serves as a lead candidate for further optimization studies.
Subject(s)
Anilides/chemical synthesis , Anilides/pharmacology , Anti-Inflammatory Agents/pharmacology , Piperidines/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Anilides/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Macrophages/drug effects , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
High content screening (HCS), the large-scale automated analysis of the temporal and spatial changes in cells and cell constituents in arrays of cells, has the potential to create enormous systems cell biology knowledge bases. HCS is being employed along with the continuum of the early drug discovery process, including lead optimization where new knowledge is being used to facilitate the decision-making process. We demonstrate methodology to build new systems cell biology knowledge using a multiplexed HCS assay, designed with the aid of knowledge-mining tools, to measure the phenotypic response of a panel of human tumor cell types to a panel of natural product-derived microtubule-targeted anticancer agents and their synthetic analogs. We show how this new systems cell biology knowledge can be used to design a lead compound optimization strategy for at least two members of the panel, (-)-laulimalide and (+)-discodermolide, that exploits cell killing activity while minimally perturbing the regulation of the cell cycle and the stability of microtubules. Furthermore, this methodology can also be applied to basic biomedical research on cells.
Subject(s)
Antineoplastic Agents/administration & dosage , Biological Assay/methods , Cell Culture Techniques/methods , Drug Evaluation, Preclinical/methods , Systems Biology/methods , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/physiology , Artificial Intelligence , Biological Assay/instrumentation , Cell Culture Techniques/instrumentation , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/instrumentation , Humans , Robotics/methods , Systems Biology/instrumentation , Tumor Cells, Cultured/cytologyABSTRACT
[reaction: see text] An efficient and versatile method for stereoselective synthesis of (E)-3,3-(diarylmethylene)indolinones by a palladium-catalyzed tandem Heck-carbocyclization/Suzuki-coupling sequence is presented. Factors influencing yield and selectivity, namely catalyst, coordinating ligand, and solvent, are detailed.
ABSTRACT
An enantioselective total synthesis of the naturally occurring anticancer agent (-)-laulimalide is described. The synthesis is characterized by extensive use of new reaction methodologies based on catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions and transformations of the derived enantioenriched beta-lactones. The synthesis also incorporates a unique allenylstannane glycal acetate alkylation and chemoselective ring-closing metathesis reaction.