ABSTRACT
Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and related phenotypes in several neurodegenerative disease models. KMO is thus a promising candidate drug target for these disorders, but known inhibitors are not brain permeable. Here, 19 new KMO inhibitors have been identified. One of these (1) is neuroprotective in a Drosophila HD model but is minimally brain penetrant in mice. The prodrug variant (1b) crosses the blood-brain barrier, releases 1 in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which KP likely plays a role, including HD, Alzheimer's disease, and Parkinson's disease.
Subject(s)
Brain/drug effects , Kynurenine 3-Monooxygenase/metabolism , Neurodegenerative Diseases/metabolism , Animals , Blood-Brain Barrier , Brain/metabolism , Enzyme Inhibitors/pharmacology , Hydrogen Peroxide/metabolism , Kynurenine 3-Monooxygenase/antagonists & inhibitors , Mice , Neurodegenerative Diseases/enzymologyABSTRACT
Triage of a set of antimalaria hit compounds, identified through high throughput screening against the Chloroquine sensitive (3D7) and resistant (Dd2) parasite Plasmodium falciparum strains identified several novel chemotypes suitable for hit-to-lead chemistry investigation. The set was further refined through investigation of their in vitro ADME properties, which identified templates with good potential to be developed further as antimalarial agents. One example was profiled in an in vivo murine Plasmodium berghei model of malaria infection.
Subject(s)
Diffusion of Innovation , Drug Discovery/methods , Neglected Diseases/drug therapy , Patents as Topic , Cooperative Behavior , Drug Discovery/legislation & jurisprudence , Drug Industry/legislation & jurisprudence , Humans , Information Dissemination/legislation & jurisprudence , Information Dissemination/methods , Patents as Topic/legislation & jurisprudence , Tropical Medicine/methodsABSTRACT
Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-α production from isolated human peripheral blood mononuclear cells.
Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Heterocyclic Compounds/chemistry , Phosphodiesterase Inhibitors/chemistry , Pyrazoles/chemistry , Pyridines/chemistry , Binding Sites , Computer Simulation , Crystallography, X-Ray , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Humans , Models, Chemical , Models, Molecular , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Protein Structure, Tertiary , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Ru- and Mo-based catalysts can be used in ring closing metathesis (RCM) reactions to synthesise cyclic phosphines protected as their borane complexes. The compatibility of the Schrock Mo-catalyst and the N-heterocyclic carbene Ru-catalysts with this class of substrates is particularly noteworthy as asymmetric RCM (ARCM) is now emerging as a new tool for the preparation of homochiral phosphines. One of the key results is that the Mo-catalyst allows the ring closure of the unprotected diallylphenylphosphine with 95% conversion.
