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Start Over Author "Anja Limberg" Topic pharmacology
4 results on '"Anja Limberg"'

1. Discovery of RO7185876, a Highly Potent γ-Secretase Modulator (GSM) as a Potential Treatment for Alzheimer’s Disease

Author

Michael Reutlinger, Georg Schmitt, Roland Jakob-Roetne, Anja Limberg, Hasane Ratni, Werner Neidhart, Solen Pichereau, Caterina Bissantz, Karlheinz Baumann, Rosa-Maria Rodriguez-Sarmiento, Mingqiu Lu, Bjoern Bartels, Irene Gerlach, André Alker, Eric Zhang, and Chen Weichun

Subjects
010405 organic chemistry, Drug discovery, Chemistry, Organic Chemistry, γ secretase modulator, Disease, Pharmacology, 01 natural sciences, Biochemistry, In vitro, 0104 chemical sciences, Range finding, 010404 medicinal & biomolecular chemistry, In vivo, Drug Discovery, Gamma secretase
Abstract

[Image: see text] γ-Secretase (GS) is a key target for the potential treatment of Alzheimer’s disease. While inhibiting GS led to serious side effects, its modulation holds a lot of potential to deliver a safe treatment. Herein, we report the discovery of a potent and selective gamma secretase modulator (GSM) (S)-3 (RO7185876), belonging to a novel chemical class, the triazolo-azepines. This compound demonstrates an excellent in vitro and in vivo DMPK profile. Furthermore, based on its in vivo efficacy in a pharmacodynamic mouse model and the outcome of the dose range finding (DRF) toxicological studies in two species, this compound was selected to undergo entry in human enabling studies (e.g., GLP toxicology and scale up activities).

Published
2020

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

Author

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

Subjects
Models, Molecular, Aurora inhibitor, Aurora A kinase, Administration, Oral, Biological Availability, Antineoplastic Agents, macromolecular substances, Protein Serine-Threonine Kinases, Pyrazole, Pharmacology, Crystallography, X-Ray, Structure-Activity Relationship, chemistry.chemical_compound, Aurora kinase, Aurora Kinases, Cell Line, Tumor, Drug Discovery, Aurora Kinase B, Humans, Structure–activity relationship, Molecular Structure, Kinase, enzymes and coenzymes (carbohydrates), chemistry, Biochemistry, Cell culture, embryonic structures, Phthalazines, Pyrazoles, Molecular Medicine, Drug Screening Assays, Antitumor, biological phenomena, cell phenomena, and immunity
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.

Published
2010

3. A Pentacyclic Aurora Kinase Inhibitor (AKI-001) with High in Vivo Potency and Oral Bioavailability

Author

Laura Corson, Thomas Hunsaker, Yingqing Ran, Andrea G. Cochran, Elizabeth Blackwood, Hans-Willi Krell, Leslie Walker, Jun Li, Birong Zhang, Aihe Zhou, Jason Halladay, Thomas E. Rawson, Bing-Yan Zhu, Carter Fields, Brian Safina, Mark Ultsch, Matthias Rüth, Tracy Kleinheinz, Angela McNutt, Dan Burdick, Jun Liang, Jason Drummond, Petra Rüger, Christian Wiesmann, Bernhard Goller, Guy Georges, Gail Lewis Phillips, Anja Limberg, John Moffat, and Jenna Dotson

Subjects
Models, Molecular, Lactams, Aurora B kinase, Aurora inhibitor, Administration, Oral, Biological Availability, Protein Serine-Threonine Kinases, Pharmacology, Crystallography, X-Ray, Heterocyclic Compounds, 4 or More Rings, Mice, Dogs, Aurora kinase, Aurora Kinases, In vivo, Cell Line, Tumor, Drug Discovery, Animals, Aurora Kinase B, Humans, Potency, Protein Kinase Inhibitors, IC50, Aurora Kinase A, Molecular Structure, Chemistry, Rats, Biochemistry, embryonic structures, Molecular Medicine, Benzimidazoles, biological phenomena, cell phenomena, and immunity
Abstract

Aurora kinase inhibitors have attracted a great deal of interest as a new class of antimitotic agents. We report a novel class of Aurora inhibitors based on a pentacyclic scaffold. A prototype pentacyclic inhibitor 32 (AKI-001) derived from two early lead structures improves upon the best properties of each parent and compares favorably to a previously reported Aurora inhibitor, 39 (VX-680). The inhibitor exhibits low nanomolar potency against both Aurora A and Aurora B enzymes, excellent cellular potency (IC50 < 100 nM), and good oral bioavailability. Phenotypic cellular assays show that both Aurora A and Aurora B are inhibited at inhibitor concentrations sufficient to block proliferation. Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model.

Published
2008

4. P1‐246: N‐heteroaryl‐piperidinyl‐4‐amines as selective GAMMA secretase modulators for the potential treatment of Alzheimer's disease

Author

Karlheinz Baumann, Pascale David-Pierson, Helmut Jacobsen, Anja Limberg, Erwin Goetschi, Synese Jolidon, Henner Knust, Luke Green, Andrew Thomas, Thomas Luebbers, and Alexander Flohr

Subjects
Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Chemistry, Health Policy, Neurology (clinical), Disease, Geriatrics and Gerontology, Pharmacology, Gamma secretase
Published
2012

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