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1.
ACS Chem Neurosci ; 8(9): 1995-2004, 2017 09 20.
Article in English | MEDLINE | ID: mdl-28609096

ABSTRACT

To enable the clinical development of our CNS casein kinase 1 delta/epsilon (CK1δ/ε) inhibitor project, we investigated the possibility of developing a CNS positron emission tomography (PET) radioligand. For this effort, we focused our design and synthesis efforts on the initial CK1δ/ε inhibitor HTS hits with the goal of identifying a compound that would fulfill a set of recommended PET ligand criteria. We identified [3H]PF-5236216 (9) as a tool ligand that meets most of the key CNS PET attributes including high CNS MPO PET desirability score and kinase selectivity, CNS penetration, and low nonspecific binding. We further used [3H]-9 to determine the binding affinity for PF-670462, a literature CK1δ/ε inhibitor tool compound. Lastly, [3H]-9 was used to measure in vivo target occupancy (TO) of PF-670462 in mouse and correlated TO with CK1δ/ε in vivo pharmacology (circadian rhythm modulation).


Subject(s)
Brain/diagnostic imaging , Brain/metabolism , Casein Kinase I/antagonists & inhibitors , Lactams , Positron-Emission Tomography , Radiopharmaceuticals , Animals , COS Cells , Casein Kinase I/metabolism , Chlorocebus aethiops , Circadian Rhythm/drug effects , Circadian Rhythm/physiology , Drug Design , Humans , Lactams/chemical synthesis , Lactams/pharmacokinetics , Male , Mice, Inbred C57BL , Molecular Structure , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacokinetics , Random Allocation
2.
Brain Behav Immun ; 64: 285-295, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28438557

ABSTRACT

Inhibitors of phosphodiesterase-4 (PDE4) have been approved for the treatment of inflammatory disorders, but are associated with dose-limiting nausea and vomiting. These side effects are hypothesized to be mediated by inhibition of the PDE4D isozyme. Here we demonstrate the anti-inflammatory effects of the novel brain penetrant PDE4D-sparing PDE4 inhibitor, ABI-4. ABI-4 was a potent (EC50∼14nM) inhibitor of lipopolysaccharide (LPS) induced TNF-α release from mouse microglia and human PBMCs. ABI-4 (0.32mg/kg) blocked LPS-induced release of pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6) in blood and brain of mice. In a rat model of endotoxin induced uveitis, ABI-4 (0.03-0.3mg/kg) demonstrated steroid-like efficacy in preventing leucocyte infiltration of the aqueous humor when administered 4h after LPS. LPS (0.32mg/kg×5days) caused a 30% upregulation of translocator protein (TSPO) binding which was prevented by co-administration of ABI-4 (0.32mg/kg). In a paradigm to assess motivation, LPS (0.32mg/kg) reduced the number of rewards received, whereas the effect was significantly blunted in mice dosed with ABI-4 (P<0.05) or in PDE4B-/- mice. PDE4B was also shown to modulate brain and plasma levels of TNF-α and IL-1ß in aged mice. Aged mice dosed chronically with ABI-4 (0.32mg/kg) as well as aged PDE4B-/- mice, had significantly lower levels of TNF-α and IL-1ß in brain and plasma relative to vehicle treated or PDE4+/+ mice. Together these data demonstrate that the PDE4D sparing, PDE4 inhibitor, ABI-4 retains potency and efficacy in exerting anti-inflammatory effects. This mechanism warrants further investigation in human disorders involving neuroinflammation.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Brain/drug effects , Encephalitis/drug therapy , Inflammation/drug therapy , Phosphodiesterase 4 Inhibitors/administration & dosage , Animals , Brain/metabolism , Encephalitis/chemically induced , Encephalitis/metabolism , Humans , Inflammation/chemically induced , Inflammation/metabolism , Inflammation Mediators/metabolism , Isoenzymes/administration & dosage , Lipopolysaccharides , Male , Mice, Inbred C57BL , Microglia/drug effects , Microglia/metabolism , Motivation/drug effects , Rats, Inbred Lew
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