Search

The expanded polyglutamine-containing mutant huntingtin (mHTT) protein is implicated in neuronal degeneration of medium spiny neurons in Huntington's disease (HD) for which multiple therapeutic approaches are currently being evaluated to eliminate or reduce mHTT. Development of effective and orthogonal biomarkers will ensure accurate assessment of the safety and efficacy of pharmacologic interventions. We have identified and optimized a class of ligands that bind to oligomerized/aggregated mHTT, which is a hallmark in the HD postmortem brain. These ligands are potentially useful imaging biomarkers for HD therapeutic development in both preclinical and clinical settings. We describe here the optimization of the benzo[4,5]imidazo[1,2-a]pyrimidine series that show selective binding to mHTT aggregates over Aβ- and/or tau-aggregates associated with Alzheimer's disease pathology. Compound [11C]-2 was selected as a clinical candidate based on its high free fraction in the brain, specific binding in the HD mouse model, and rapid brain uptake/washout in nonhuman primate positron emission tomography imaging studies.

Mutant huntingtin (mHTT) protein carrying the elongated N-terminal polyglutamine (polyQ) tract misfolds and forms protein aggregates characteristic of Huntington's disease (HD) pathology. A high-affinity ligand specific for mHTT aggregates could serve as a positron emission tomography (PET) imaging biomarker for HD therapeutic development and disease progression. To identify such compounds with binding affinity for polyQ aggregates, we embarked on systematic structural activity studies; lead optimization of aggregate-binding affinity, unbound fractions in brain, permeability, and low efflux culminated in the discovery of compound 1, which exhibited target engagement in autoradiography (ARG) studies in brain slices from HD mouse models and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates (NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for imaging of mHTT aggregates. [11C]-1R is now being advanced to human trials as a first-in-class HD PET radiotracer.

(1,1-Dioxo-2H-[1,2,4]benzothiadiazin-3-yl) azolo[1,5-a]pyridine and azolo[1,5-a]pyrimidine derivatives have been investigated as potential anti-HCV drugs. Their synthesis, HCV NS5B polymerase inhibition, and replicon activity are discussed.

A novel palladium catalysed three-component process is described involving an allene, an aryl iodide containing an activated alkene and TMSN 3 . The cascade proceeds via a (π-allyl)palladium species which is intercepted by azide anion followed by stereoselective intramolecular 1,3-dipolar cycloaddition of the organoazide to afford substituted triazolo- and tetrazolo-tetrahydroisoquinolines in good yield. These latter products undergo extrusion of nitrogen to afford isoquinolines at 100 °C.

A novel palladium catalysed three-component cascade process is described involving allenylation of an aryl iodide to generate a (π-allyl)palladium species which is intercepted by a carbon or nitrogen nucleophile followed by intramolecular Michael addition to afford carbo- and heterocycles in good yield.

A novel palladium-catalysed three component cascade process is described involving carbonylation of an aryl iodide to generate an acyl palladium species which is intercepted by a primary aliphatic/aromatic amine, amide or sulfonamide followed by intramolecular Michael addition to afford 3-substituted isoindolin-1-ones in good yield.

A 3-component cascade synthesis of bis(2-arylallyl) tertiary amines from aryl iodide, allene and primary aliphatic amines is described; chiral amines give analogous products with no detectable racemisation; mixtures of two different aryl iodides can be utilised to give the mixed tertiary amines as the sole, or major, product; the reaction is sensitive to stereoelectronic effects which lead to mono(2-arylallyl) secondary amines.

Cyclopalladated phosphine free pyrazole complexes 1 and benzothiazole complexes 2 are excellent catalysts for the Heck vinylation of aryl iodides and termolecular queuing cascades, leading to turnover numbers of >106 in some cases, at moderate temperatures; these catalysts show high thermal stability and are not sensitive to moisture and air.

2-Haloaryl aldehydes and ketones react with allene (1 atm) in the presence of 2 mol% of a non-phosphine cyclopalladated catalyst to afford cyclopentenols and cyclohexenols via nucleophilic cyclisation of intermediate π-allylpalladium species. A possible mechanism for this unusual reactivity is suggested.

2-Haloaryl aldehydes and ketones react with allene (1 atm) in the presence of 2 mol% of a non-phosphine cyclopalladated catalyst to afford cyclopentenols and cyclohexenols via nucleophilic cyclisation of intermediate π-allylpalladium species. A possible mechanism for this unusual reactivity is suggested.

Cyclopalladated phosphine free pyrazole complexes 1 and benzothiazole complexes 2 are excellent catalysts for the Heck vinylation of aryl iodides and termolecular queuing cascades, leading to turnover numbers of >106 in some cases, at moderate temperatures; these catalysts show high thermal stability and are not sensitive to moisture and air.