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4 results on '"Michael E. Prime"'

1. Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates

Author

Frank Herrmann, Manuela Hessmann, Sabine Schaertl, Karola Berg-Rosseburg, Christopher J Brown, Galina Bursow, Anass Chiki, Andreas Ebneth, Miriam Gehrmann, Nicole Hoeschen, Madlen Hotze, Stefanie Jahn, Peter D Johnson, Vinod Khetarpal, Alex Kiselyov, Karsten Kottig, Stefanie Ladewig, Hilal Lashuel, Sven Letschert, Matthew R Mills, Kathrin Petersen, Michael E Prime, Christoph Scheich, Gerhard Schmiedel, John Wityak, Longbin Liu, Celia Dominguez, Ignacio Muñoz-Sanjuán, and Jonathan A Bard

Subjects
Medicine, Science
Abstract

Abstract Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents. We recently reported the development of PET tracers CHDI-180 and CHDI-626 as suitable for imaging mHTT aggregates, and here we present an in-depth pharmacological investigation of their binding characteristics. We have implemented an array of in vitro and ex vivo radiometric binding assays using recombinant HTT, brain homogenate-derived HTT aggregates, and brain sections from mouse HD models and humans post-mortem to investigate binding affinities and selectivity against other pathological proteins from indications such as Alzheimer’s disease and spinocerebellar ataxia 1. Radioligand binding assays and autoradiography studies using brain homogenates and tissue sections from HD mouse models showed that CHDI-180 and CHDI-626 specifically bind mHTT aggregates that accumulate with age and disease progression. Finally, we characterized CHDI-180 and CHDI-626 regarding their off-target selectivity and binding affinity to beta amyloid plaques in brain sections and homogenates from Alzheimer’s disease patients.

Published
2021
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2. Development of a ligand for in vivo imaging of mutant huntingtin in Huntington’s disease

Author

Daniele Bertoglio, Jonathan Bard, Manuela Hessmann, Longbin Liu, Annette Gärtner, Stef De Lombaerde, Britta Huscher, Franziska Zajicek, Alan Miranda, Finn Peters, Frank Herrmann, Sabine Schaertl, Tamara Vasilkovska, Christopher J. Brown, Peter D. Johnson, Michael E. Prime, Matthew R. Mills, Annemie Van der Linden, Ladislav Mrzljak, Vinod Khetarpal, Yuchuan Wang, Deanna M. Marchionini, Mette Skinbjerg, Jeroen Verhaeghe, Celia Dominguez, Steven Staelens, and Ignacio Munoz-Sanjuan

Subjects
General Medicine, Human medicine, Biology
Abstract

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin ( HTT ) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) tract. Whereas several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, methods to visualize mHTT protein species in the living brain are lacking. Here, we demonstrate the development and characterization of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11 C ([ 11 C]CHDI-180R) allowed noninvasive monitoring of mHTT pathology in the brain and could track region- and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression in a rodent model. We further showed that in these animals, therapeutic agents that lowered mHTT in the striatum had a functional restorative effect that could be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.

Published
2022

3. Synthesis of α-hydroxy-β,β-difluoro-γ-ketoesters via [3,3]sigmatropic rearrangements

Author

Michael J. Broadhurst, Jonathan M. Percy, Samantha J. Brown, and Michael E. Prime

Subjects
chemistry.chemical_classification, chemistry.chemical_compound, Allylic rearrangement, Ketone, chemistry, Fragmentation (mass spectrometry), Silylation, Ketene, Organic chemistry, Chelation, QD
Abstract

Readily available γ,γ-difluorinated allylic alcohols obtained from trifluoroethanol were esterified efficiently. Exposure to strong base (LDA) afforded the ester enolates, in which chelation both controlled configuration and stabilised against fragmentation, which were trapped as their silyl ketene acetals. Rearrangement occurred to afford base-sensitive acid products. Esterification under mild conditions afforded the purifiable methyl esters in which the masked ketone had been released. Educts with either a benzyloxy or an allyloxy group at the α-position could be deprotected releasing the alcohols.

Published
2000

4. Phthalazinone Pyrazoles as Potent, Selective, and Orally Bioavailable Inhibitors of Aurora-A Kinase.

Author

Michael E. Prime, Stephen M. Courtney, Frederick A. Brookfield, Richard W. Marston, Victoria Walker, Justin Warne, Andrew E. Boyd, Norman A. Kairies, Wolfgang von der Saal, Anja Limberg, Guy Georges, Richard A. Engh, Bernhard Goller, Petra Rueger, and Matthias Rueth

Subjects
*PYRAZOLES, *DRUG synergism, *DRUG bioavailability, *AURORAS, *PROTEIN kinases, *MITOSIS, *TUMOR growth, *APOPTOSIS, *CANCER cell proliferation
Abstract

The inhibition of Aurora kinases in order to arrest mitosis and subsequently inhibit tumor growth via apoptosis of proliferating cells has generated significant discussion within the literature. We report a novel class of Aurora kinase inhibitors based upon a phthalazinone pyrazole scaffold. The development of the phthalazinone template resulted in a potent Aurora-A selective series of compounds (typically >1000-fold selectivity over Aurora-B) that display good pharmacological profiles with significantly improved oral bioavailability compared to the well studied Aurora inhibitor VX-680. [ABSTRACT FROM AUTHOR]

Published
2011
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