ABSTRACT
Small molecule isoindoline and tetrahydroisoquinoline derivatives have been identified as selective agonists of human peroxisome proliferator-activated receptor δ (PPARδ. Compound 18 demonstrated efficacy in a biomarker for increased fatty acid oxidation, with upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4) in human primary myotubes.
Subject(s)
Indoles/chemistry , PPAR delta/agonists , Tetrahydroisoquinolines/chemistry , Binding Sites , Catalytic Domain , Computer Simulation , Humans , Indoles/chemical synthesis , Indoles/pharmacology , PPAR delta/metabolism , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , Structure-Activity Relationship , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/pharmacologyABSTRACT
By combining the capabilities of advanced sample preparation methodologies with the latest generation of secondary ion mass spectrometry instrumentation, we show that chemical information on the distribution of even dilute species in biological samples can be obtained with spatial resolutions of better than 100 nm. Here, we show the distribution of nickel and other elements in leaf tissue of the nickel hyperaccumulator plant Alyssum lesbiacum prepared by high-pressure freezing and freeze substitution.
Subject(s)
Brassicaceae/chemistry , Nanotechnology/instrumentation , Nickel/analysis , Spectrometry, Mass, Secondary Ion/methods , Brassicaceae/cytology , Brassicaceae/ultrastructure , Microscopy, Electron, Transmission , Plant Leaves/chemistry , Plant Leaves/cytology , Plant Leaves/ultrastructure , Spectrometry, Mass, Secondary Ion/instrumentation , Spectrophotometry, Atomic , VacuolesABSTRACT
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.
Subject(s)
Adenosine Triphosphate/therapeutic use , Adenosine/analogs & derivatives , Membrane Proteins/antagonists & inhibitors , Purinergic P2 Receptor Antagonists , Thrombosis/prevention & control , Adenosine/therapeutic use , Administration, Oral , Animals , Humans , Receptors, Purinergic P2Y12 , TicagrelorABSTRACT
We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.
