477543-38-7Relevant academic research and scientific papers
Heteroaromatic Inhibitors of the Astacin Proteinases Meprin α, Meprin β and Ovastacin Discovered by a Scaffold-Hopping Approach
Tan, Kathrin,J?ger, Christian,K?rschgen, Hagen,Geissler, Stefanie,Schlenzig, Dagmar,Buchholz, Mirko,St?cker, Walter,Ramsbeck, Daniel
supporting information, p. 976 - 988 (2020/12/25)
Astacin metalloproteinases, in particular meprins α and β, as well as ovastacin, are emerging drug targets. Drug-discovery efforts have led to the development of the first potent and selective inhibitors in the last few years. However, the most recent compounds are based on a highly flexible tertiary amine scaffold that could cause metabolic liabilities or decreased potency due to the entropic penalty upon binding to the target. Thus, the aim of this study was to discover novel conformationally constrained scaffolds as starting points for further inhibitor optimization. Shifting from flexible tertiary amines to rigid heteroaromatic cores resulted in a boost in inhibitory activity. Moreover, some compounds already exhibited higher activity against individual astacin proteinases compared to recently reported inhibitors and also a favorable off-target selectivity profile, thus qualifying them as very suitable chemical probes for target validation.
Discovery of benzimidazole derivatives as modulators of mitochondrial function: A potential treatment for Alzheimer's disease
Kim, TaeHun,Yang, Ha Yun,Park, Beoung Gun,Jung, Seo Yun,Park, Jong-Hyun,Park, Ki Duk,Min, Sun-Joon,Tae, Jinsung,Yang, Hyejin,Cho, Suengmok,Cho, Sung Jin,Song, Hyundong,Mook-Jung, Inhee,Lee, Jiyoun,Pae, Ae Nim
supporting information, p. 1172 - 1192 (2016/11/23)
In this study, we designed a library of compounds based on the structures of well-known ligands of the 18 kDa translocator protein (TSPO), one of the putative components of the mPTP. We performed diverse mitochondrial functional assays to assess their ability to restore cells from Aβ-induced toxicity in vitro and in vivo. Among tested compounds, compound 25 effectively improved cognitive function in animal models of AD. Given the excellent in vitro and in vivo activity and a favorable pharmacokinetic profile of compound 25, we believe that it can serve as a promising lead compound for a potential treatment option for AD.
SUBSTITUTED BENZIMIDAZOLIUM, PYRIDO-IMIDAZOLIUM, OR PYRAZINO-IMIDAZOLIUM COMPOUNDS AS CHEMOTHERAPEUTICS
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, (2017/08/01)
Provided herein are compounds of the formula:(I) wherein: R1, R2, R3, R4, R5, X, A1, A2, A3, and A4 are as defined herein. In some aspects, these compounds may be used to treat cancer and other hyperproliferative disease. In some aspects, compositions, methods of treatment, and methods of synthesis are also provided herein.
Benzimidazoles for the treatment of cancer
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Paragraph 0101-0102, (2014/03/22)
The present invention relates to novel substituted benzimidazoles and stereoisomeric forms, prodrugs, solvates, hydrates and/or pharmaceutically acceptable salts of these compounds as well as pharmaceutical compositions containing at least one of these substituted benzimidazoles together with pharmaceutically acceptable carrier, excipient and/or diluents. Said novel substituted benzimidazoles binding to the prenyl binding pocket of PDEδ have been identified as useful for the prophylaxis and treatment of cancer by the inhibition of the binding of PDEδ to K-Ras and of oncogenic Ras signalling in cells by altering its localization leading to cell death or inhibition of proliferation.
BENZIMIDAZOLES FOR THE TREATMENT OF CANCER
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Page/Page column 64-65, (2014/03/22)
The present invention relates to novel substituted benzimidazoles and stereoisomeric forms, prodrugs, solvates, hydrates and/or pharmaceutically acceptable salts of these compounds as well as pharmaceutical compositions containing at least one of these substituted benzimidazoles together with pharmaceutically acceptable carrier, excipient and/or diluents. Said novel substituted benzimidazoles binding to the prenyl binding pocket of PDEδ have been identified as useful for the prophylaxis and treatment of cancer by the inhibition of the binding of PDEδ to K-Ras and of oncogenic Ras signalling in cells by altering its localization leading to cell death or inhibition of proliferation.
BENZIMIDAZOLE DERIVATIVES AS MITOCHONDRIAL FUNCTION MODULATORS
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Paragraph 0155-0156, (2014/05/07)
Provided are a benzimidazole derivative modulating mitochondrial functions and having pharmaceutical activity as a neuro-protective agent, and a pharmaceutical composition including the compound as an active ingredient.
Structure guided design and kinetic analysis of highly potent benzimidazole inhibitors targeting the PDEδ prenyl binding site
Zimmermann, Gunther,Schultz-Fademrecht, Carsten,Küchler, Philipp,Murarka, Sandip,Ismail, Shehab,Triola, Gemma,Nussbaumer, Peter,Wittinghofer, Alfred,Waldmann, Herbert
, p. 5435 - 5448 (2014/07/08)
K-Ras is one of the most frequently mutated signal transducing human oncogenes. Ras signaling activity requires correct cellular localization of the GTPase. The spatial organization of K-Ras is controlled by the prenyl binding protein PDEδ, which enhances Ras diffusion in the cytosol. Inhibition of the Ras-PDEδ interaction by small molecules impairs Ras localization and signaling. Here we describe in detail the identification and structure guided development of Ras-PDEδ inhibitors targeting the farnesyl binding pocket of PDEδ with nanomolar affinity. We report kinetic data that characterize the binding of the most potent small molecule ligands to PDEδ and prove their binding to endogenous PDEδ in cell lysates. The PDEδ inhibitors provide promising starting points for the establishment of new drug discovery programs aimed at cancers harboring oncogenic K-Ras.
