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  1. Article ; Online: Selective and Stepwise Functionalization of the Pyridazine Scaffold by Using Thio-Substituted Pyridazine Building Blocks.

    Hamze, Clémence / Brossier, Julie / Karaghiosoff, Konstantin / Godineau, Edouard / Knochel, Paul

    Chemistry (Weinheim an der Bergstrasse, Germany)

    2023  Volume 29, Issue 63, Page(s) e202302156

    Abstract: We described a regioselective tri- and tetra-functionalization of the pyridazine scaffold using two readily available building blocks: 3-alkylthio-6-chloropyridazine and 3,4-bis(methylthio)-6-chloropyridazine by performing selective metalations with ... ...

    Abstract We described a regioselective tri- and tetra-functionalization of the pyridazine scaffold using two readily available building blocks: 3-alkylthio-6-chloropyridazine and 3,4-bis(methylthio)-6-chloropyridazine by performing selective metalations with TMPMgCl ⋅ LiCl and catalyst-tuned cross-coupling reactions with arylzinc halides. Several of the resulting pyridazines were converted into more elaborated N-heterocycles such as thieno[2,3-c]pyridazines and 1H-pyrazolo[3,4-c]pyridazines.
    Language English
    Publishing date 2023-10-03
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1478547-X
    ISSN 1521-3765 ; 0947-6539
    ISSN (online) 1521-3765
    ISSN 0947-6539
    DOI 10.1002/chem.202302156
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A Markov model of fibrosis development in nonalcoholic fatty liver disease predicts fibrosis progression in clinical cohorts.

    Knöchel, Jane / Bergenholm, Linnéa / Ibrahim, Eman / Kechagias, Stergios / Hansson, Sara / Liljeblad, Mathias / Nasr, Patrik / Carlsson, Björn / Ekstedt, Mattias / Ueckert, Sebastian

    CPT: pharmacometrics & systems pharmacology

    2023  Volume 12, Issue 12, Page(s) 2038–2049

    Abstract: Disease progression in nonalcoholic steatohepatitis (NASH) is highly heterogenous and remains poorly understood. Fibrosis stage is currently the best predictor for development of end-stage liver disease and mortality. Better understanding and quantifying ...

    Abstract Disease progression in nonalcoholic steatohepatitis (NASH) is highly heterogenous and remains poorly understood. Fibrosis stage is currently the best predictor for development of end-stage liver disease and mortality. Better understanding and quantifying the impact of factors affecting NASH and fibrosis is essential to inform a clinical study design. We developed a population Markov model to describe the transition probability between fibrosis stages and mortality using a unique clinical nonalcoholic fatty liver disease cohort with serial biopsies over 3 decades. We evaluated covariate effects on all model parameters and performed clinical trial simulations to predict the fibrosis progression rate for external clinical cohorts. All parameters were estimated with good precision. Age and diagnosis of type 2 diabetes (T2D) were found to be significant predictors in the model. Increase in hepatic steatosis between visits was the most important predictor for progression of fibrosis. Fibrosis progression rate (FPR) was twofold higher for fibrosis stages 0 and 1 (F0-1) compared to fibrosis stage 2 and 3 (F2-3). A twofold increase in FPR was observed for T2D. A two-point steatosis worsening increased the FPR 11-fold. Predicted fibrosis progression was in good agreement with data from external clinical cohorts. Our fibrosis progression model shows that patient selection, particularly initial fibrosis stage distribution, can significantly impact fibrosis progression and as such the window for assessing drug efficacy in clinical trials. Our work highlights the increase in hepatic steatosis as the most important factor in increasing FPR, emphasizing the importance of well-defined lifestyle advise for reducing variability in NASH progression during clinical trials.
    MeSH term(s) Humans ; Non-alcoholic Fatty Liver Disease/epidemiology ; Liver ; Diabetes Mellitus, Type 2/drug therapy ; Disease Progression ; Fibrosis
    Language English
    Publishing date 2023-10-03
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2697010-7
    ISSN 2163-8306 ; 2163-8306
    ISSN (online) 2163-8306
    ISSN 2163-8306
    DOI 10.1002/psp4.13052
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Cobalt-Catalyzed Cross-Couplings between Alkenyl Acetates and Aryl or Alkenyl Zinc Pivalates.

    Li, Jie / Knochel, Paul

    Angewandte Chemie (International ed. in English)

    2018  Volume 57, Issue 35, Page(s) 11436–11440

    Abstract: ... ...

    Abstract CoBr
    Language English
    Publishing date 2018-07-27
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.201805486
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  4. Article ; Online: Diastereo- and Enantioselective Cross-Couplings of Secondary Alkylcopper Reagents with 3-Halogeno-Unsaturated Carbonyl Derivatives.

    Kremsmair, Alexander / Skotnitzki, Juri / Knochel, Paul

    Chemistry (Weinheim an der Bergstrasse, Germany)

    2020  Volume 26, Issue 52, Page(s) 11971–11973

    Abstract: Chiral secondary alkylcopper reagents were prepared from the corresponding alkyl iodides with retention of configuration by an I/Li-exchange using tBuLi (-100 °C, 1 min) followed by a transmetalation with CuBr⋅P(OEt) ...

    Abstract Chiral secondary alkylcopper reagents were prepared from the corresponding alkyl iodides with retention of configuration by an I/Li-exchange using tBuLi (-100 °C, 1 min) followed by a transmetalation with CuBr⋅P(OEt)
    Language English
    Publishing date 2020-09-02
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1478547-X
    ISSN 1521-3765 ; 0947-6539
    ISSN (online) 1521-3765
    ISSN 0947-6539
    DOI 10.1002/chem.202002297
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  5. Article ; Online: Phase Noise of SAW Delay Line Magnetic Field Sensors.

    Durdaut, Phillip / Müller, Cai / Kittmann, Anne / Schell, Viktor / Bahr, Andreas / Quandt, Eckhard / Knöchel, Reinhard / Höft, Michael / McCord, Jeffrey

    Sensors (Basel, Switzerland)

    2021  Volume 21, Issue 16

    Abstract: Surface acoustic wave (SAW) sensors for the detection of magnetic fields are currently being studied scientifically in many ways, especially since both their sensitivity as well as their detectivity could be significantly improved by the utilization of ... ...

    Abstract Surface acoustic wave (SAW) sensors for the detection of magnetic fields are currently being studied scientifically in many ways, especially since both their sensitivity as well as their detectivity could be significantly improved by the utilization of shear horizontal surface acoustic waves, i.e., Love waves, instead of Rayleigh waves. By now, low-frequency limits of detection (LOD) below 100 pT/Hz can be achieved. However, the LOD can only be further improved by gaining a deep understanding of the existing sensor-intrinsic noise sources and their impact on the sensor's overall performance. This paper reports on a comprehensive study of the inherent noise of SAW delay line magnetic field sensors. In addition to the noise, however, the sensitivity is of importance, since both quantities are equally important for the LOD. Following the necessary explanations of the electrical and magnetic sensor properties, a further focus is on the losses within the sensor, since these are closely linked to the noise. The considered parameters are in particular the ambient magnetic bias field and the input power of the sensor. Depending on the sensor's operating point, various noise mechanisms contribute to f0 white phase noise, f-1 flicker phase noise, and f-2 random walk of phase. Flicker phase noise due to magnetic hysteresis losses, i.e. random fluctuations of the magnetization, is usually dominant under typical operating conditions. Noise characteristics are related to the overall magnetic and magnetic domain behavior. Both calculations and measurements show that the LOD cannot be further improved by increasing the sensitivity. Instead, the losses occurring in the magnetic material need to be decreased.
    Language English
    Publishing date 2021-08-21
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2052857-7
    ISSN 1424-8220 ; 1424-8220
    ISSN (online) 1424-8220
    ISSN 1424-8220
    DOI 10.3390/s21165631
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Transcription patterns of four different fork head/HNF-3 related genes (XFD-4, 6, 9 and 10) in Xenopus laevis embryos.

    Scheucher, Michaela / Dege, Petra / Lef, Jutta / Hille, Sigurd / Knöchel, Walter

    Roux's archives of developmental biology : the official organ of the EDBO

    2017  Volume 204, Issue 3, Page(s) 203–211

    Abstract: We have isolated and sequenced four different members of the Xenopus fork head domain related multigene family (XFD-4, 6, 9 and 10). These genes show a high degree of sequence conservation inside the evolutionary conserved fork head domain but they ... ...

    Abstract We have isolated and sequenced four different members of the Xenopus fork head domain related multigene family (XFD-4, 6, 9 and 10). These genes show a high degree of sequence conservation inside the evolutionary conserved fork head domain but they completely diverge outside this region. All four XFD genes are transcribed during embryogenesis but they are activated at different developmental stages. To investigate the localisation of transcripts we performed whole mount in situ hybridizations. We detected XFD-4 transcripts in somitogenic mesoderm, pronephros, pronephric duct, heart and the tip of the tail. XFD-6 transcripts were confined to migrating neural crest cells originating from the mesencephalon and rhombencephalon. Transcriptional activity of XFD-9 was observed in the region of rotating somites and the posterior part of the pronephric duct. XFD-10 transcripts were detected in lateral cell stripes located at the hyoid and the anterior branchial arches.
    Language English
    Publishing date 2017-03-16
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 14096-x
    ISSN 0930-035X ; 0340-0794
    ISSN 0930-035X ; 0340-0794
    DOI 10.1007/BF00241274
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  7. Article ; Online: Iron-Mediated Electrophilic Amination of Organozinc Halides using Organic Azides.

    Graßl, Simon / Singer, Johannes / Knochel, Paul

    Angewandte Chemie (International ed. in English)

    2019  Volume 59, Issue 1, Page(s) 335–338

    Abstract: A wide range of alkyl-, aryl- and heteroarylzinc halides were aminated with highly functionalized alkyl, aryl, and heterocyclic azides. The reaction proceeds smoothly at 50 °C within 1 h in the presence of ... ...

    Abstract A wide range of alkyl-, aryl- and heteroarylzinc halides were aminated with highly functionalized alkyl, aryl, and heterocyclic azides. The reaction proceeds smoothly at 50 °C within 1 h in the presence of FeCl
    Language English
    Publishing date 2019-11-19
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.201911704
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  8. Article ; Online: A case-study of model-informed drug development of a novel PCSK9 anti sense oligonucleotide. Part 1: First time in man to phase II.

    Knöchel, Jane / Nilsson, Catarina / Carlsson, Björn / Wernevik, Linda / Hofherr, Alexis / Gennemark, Peter / Jansson-Löfmark, Rasmus / Isaksson, Rikard / Rydén-Bergsten, Tina / Hamrén, Bengt / Rekić, Dinko

    CPT: pharmacometrics & systems pharmacology

    2022  Volume 11, Issue 12, Page(s) 1569–1577

    Abstract: Here, we show model-informed drug development (MIDD) of a novel antisense oligonucleotide, targeting PCSK9 for treatment of hypocholesteremia. The case study exemplifies use of MIDD to analyze emerging data from an ongoing first-in-human study, utility ... ...

    Abstract Here, we show model-informed drug development (MIDD) of a novel antisense oligonucleotide, targeting PCSK9 for treatment of hypocholesteremia. The case study exemplifies use of MIDD to analyze emerging data from an ongoing first-in-human study, utility of the US Food and Drug Administration MIDD pilot program to accelerate timelines, innovative use of competitor data to set biomarker targets, and use of MIDD to optimize sample size and dose selection, as well as to accelerate and de-risk a phase IIb study. The focus of the case-study is on the cross-functional collaboration and other key MIDD enablers that are critical to maximize the value of MIDD, rather than the technical application of MIDD.
    MeSH term(s) Humans ; Proprotein Convertase 9/genetics ; Pharmaceutical Preparations ; Oligonucleotides, Antisense/pharmacology ; Oligonucleotides, Antisense/therapeutic use ; Drug Development
    Chemical Substances PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Pharmaceutical Preparations ; Oligonucleotides, Antisense
    Language English
    Publishing date 2022-10-01
    Publishing country United States
    Document type Clinical Trial, Phase II ; Case Reports ; Research Support, Non-U.S. Gov't
    ZDB-ID 2697010-7
    ISSN 2163-8306 ; 2163-8306
    ISSN (online) 2163-8306
    ISSN 2163-8306
    DOI 10.1002/psp4.12866
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  9. Article: Chromium-Catalyzed Cross-Couplings and Related Reactions

    Li, Jie / Knochel, Paul

    Synthesis

    2019  Volume 51, Issue 10, Page(s) 2100–2106

    Abstract: Transition-metal-catalyzed cross-couplings have been recognized as a powerful tool for sustainable syntheses. Despite the fact that remarkable progress was achieved by palladium and nickel catalysis, the high price and toxicity still remained a drawback. ...

    Abstract Transition-metal-catalyzed cross-couplings have been recognized as a powerful tool for sustainable syntheses. Despite the fact that remarkable progress was achieved by palladium and nickel catalysis, the high price and toxicity still remained a drawback. Recently, naturally more abundant and less toxic low-valent chromium salts, such as Cr(II) and Cr(III) chlorides, displayed notable unique catalytic reactivity. Thus, recent progress in the field of chromium-catalyzed cross-couplings and related reactions are highlighted in the present short review until December­ 2018. 1

    Introduction and Early Chromium-Mediated Reactions 2

    Chromium-Catalyzed Cross-Couplings and Related Reactions 3

    Conclusion
    Keywords chromium ; cross-coupling ; C–H activation ; C–X formation ; homogeneous catalysis
    Language German
    Publishing date 2019-03-21
    Publisher © Georg Thieme Verlag
    Publishing place Stuttgart ; New York
    Document type Article
    ZDB-ID 2033062-5
    ISSN 1437-210X ; 0039-7881
    ISSN (online) 1437-210X
    ISSN 0039-7881
    DOI 10.1055/s-0037-1611756
    Database Thieme publisher's database

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  10. Article ; Online: (2-Ethylhexyl)sodium: A Hexane-Soluble Reagent for Br/Na-Exchanges and Directed Metalations in Continuous Flow.

    Harenberg, Johannes H / Weidmann, Niels / Wiegand, Alexander J / Hoefer, Carla A / Annapureddy, Rajasekar Reddy / Knochel, Paul

    Angewandte Chemie (International ed. in English)

    2021  Volume 60, Issue 26, Page(s) 14296–14301

    Abstract: We report the on-demand generation of hexane-soluble (2-ethylhexyl)sodium (1) from 3-(chloromethyl)heptane (2) using a sodium-packed-bed reactor under continuous flow conditions. Thus, the resulting solution of 1 is free of elemental sodium and therefore ...

    Abstract We report the on-demand generation of hexane-soluble (2-ethylhexyl)sodium (1) from 3-(chloromethyl)heptane (2) using a sodium-packed-bed reactor under continuous flow conditions. Thus, the resulting solution of 1 is free of elemental sodium and therefore suited for a range of synthetic applications. This new procedure avoids the storage of an alkylsodium and limits the handling of metallic sodium to a minimum. (2-Ethylhexyl)sodium (1) proved to be a very useful reagent and undergoes in-line Br/Na-exchanges as well as directed sodiations. The resulting arylsodium intermediates are subsequently trapped in batch with various electrophiles such as ketones, aldehydes, Weinreb-amides, imines, allyl bromides, disulfides and alkyl iodides. A reaction scale-up of the Br/Na-exchange using an in-line electrophile quench was also reported.
    Language English
    Publishing date 2021-05-03
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 2011836-3
    ISSN 1521-3773 ; 1433-7851
    ISSN (online) 1521-3773
    ISSN 1433-7851
    DOI 10.1002/anie.202103031
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