- Antibacterial sulfonimidamide-based oligopeptides as type I signal peptidase inhibitors: Synthesis and biological evaluation
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Oligopeptide boronates with a lipophilic tail are known to inhibit the type I signal peptidase in E. coli, which is a promising drug target for developing novel antibiotics. Antibacterial activity depends on these oligopeptides having a cationic modification to increase their permeation. Unfortunately, this modification is associated with cytotoxicity, motivating the need for novel approaches. The sulfonimidamide functionality has recently gained much interest in drug design and discovery, as a means of introducing chirality and an imine-handle, thus allowing for the incorporation of additional substituents. This in turn can tune the chemical and biological properties, which are here explored. We show that introducing the sulfonimidamide between the lipophilic tail and the peptide in a series of signal peptidase inhibitors resulted in antibacterial activity, while the sulfonamide isostere and previously known non-cationic analogs were inactive. Additionally, we show that replacing the sulfonamide with a sulfonimidamide resulted in decreased cytotoxicity, and similar results were seen by adding a cationic sidechain to the sulfonimidamide motif. This is the first report of incorporation of the sulfonimidamide functional group into bioactive peptides, more specifically into antibacterial oligopeptides, and evaluation of its biological effects.
- Benediktsdottir, Andrea,Cao, Sha,Hughes, Diarmaid,Lu, Lu,Mowbray, Sherry L.,Zamaratski, Edouard,Karlén, Anders,Sandstr?m, Anja
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- Illuminating a Dark Kinase: Structure-Guided Design, Synthesis, and Evaluation of a Potent Nek1 Inhibitor and Its Effects on the Embryonic Zebrafish Pronephros
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NIMA-related kinase 1 (Nek1) has lately garnered attention for its widespread function in ciliogenesis, apoptosis, and the DNA-damage response. Despite its involvement in various diseases and its potential as a cancer drug target, no directed medicinal chemistry efforts toward inhibitors against this dark kinase are published. Here, we report the structure-guided design of a potent small-molecule Nek1 inhibitor, starting from a scaffold identified by kinase cross-screening analysis. Seven lead compounds were identified in silico and evaluated for their inhibitory activity. The top compound, 10f, was further profiled for efficacy, toxicity, and bioavailability in a zebrafish polycystic kidney disease model. Administration of 10f caused the expansion of fluorescence-labeled proximal convoluted tubules, supporting our hypothesis that Nek1-inhibition causes cystic kidneys in zebrafish embryos. Compound 10f displayed insignificant inhibition in 48 of 50 kinases in a selectivity test panel. The findings provide a powerful tool to further elucidate the function and pharmacology of this neglected kinase.
- Baumann, Georg,Meckel, Tobias,B?hm, Kevin,Shih, Yung-Hsin,Dickhaut, Mirco,Reichardt, Torben,Pilakowski, Johannes,Pehl, Ulrich,Schmidt, Boris
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- BICYCLIC COMPOUNDS AND USE AS ANTIDIABETICS
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The present invention relates to novel compounds that are useful in the treatment of metabolic disorders, particularly type II diabetes mellitus and related disorders, and also to the methods for the making and use of such compounds.
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Page/Page column 54
(2010/03/02)
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- NOVEL COMPOUNDS
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The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds according to formula (I) and salts thereof. The compounds of the invention are inhibitors of kinase activity, in particular IKK2 activity.
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Page/Page column 66
(2009/10/22)
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- IMIDAZOLYL-SUBSTITUTED BENZOPHENONE COMPOUNDS
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The compounds of formula (I) in which X, Y, R1 and R2 have the meanings as given in the description are novel effective inhibitors of the inducible nitric oxide synthase.
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Page/Page column 35
(2008/06/13)
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- Inhibitors of factor Xa
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Novel compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds are useful in vitro or in vivo for preventing or treating coagulation disorders.
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