- Structure-Activity Relationship for the Picolinamide Antibacterials that Selectively Target Clostridioides difficile
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Clostridioides difficile is a leading health threat. This pathogen initiates intestinal infections during gut microbiota dysbiosis caused by oral administration of antibiotics. C. difficile is difficult to eradicate due to its ability to form spores, which are not susceptible to antibiotics. To address the urgent need for treating recurrent C. difficile infection, antibiotics that selectively target C. difficile over common gut microbiota are needed. We herein describe the class of picolinamide antibacterials which show potent and selective activity against C. difficile. The structure-activity relationship of 108 analogues of isonicotinamide 4, a compound that is equally active against methicillin-resistant Staphylococcus aureus and C. difficile, was investigated. Introduction of the picolinamide core as exemplified by analogue 87 resulted in exquisite potency and selectivity against C. difficile. The ability of the picolinamide class to selectively target C. difficile and to prevent gut dysbiosis holds promise for the treatment of recurrent C. difficile infection.
- Speri, Enrico,Qian, Yuanyuan,Janardhanan, Jeshina,Masitas, Cesar,Lastochkin, Elena,De Benedetti, Stefania,Wang, Man,Schroeder, Valerie A.,Wolter, William R.,Oliver, Allen G.,Fisher, Jed F.,Mobashery, Shahriar,Chang, Mayland
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p. 991 - 995
(2021/05/27)
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- Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors
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The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19 T790M C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.
- Engelhardt, Harald,B?se, Dietrich,Petronczki, Mark,Scharn, Dirk,Bader, Gerd,Baum, Anke,Bergner, Andreas,Chong, Eugene,D?bel, Sandra,Egger, Georg,Engelhardt, Christian,Ettmayer, Peter,Fuchs, Julian E.,Gerstberger, Thomas,Gonnella, Nina,Grimm, Andreas,Grondal, Elisabeth,Haddad, Nizar,Hopfgartner, Barbara,Kousek, Roland,Krawiec, Mariusz,Kriz, Monika,Lamarre, Lyne,Leung, Joyce,Mayer, Moriz,Patel, Nitinchandra D.,Simov, Biljana Peric,Reeves, Jonathan T.,Schnitzer, Renate,Schrenk, Andreas,Sharps, Bernadette,Solca, Flavio,Stadtmüller, Heinz,Tan, Zhulin,Wunberg, Tobias,Zoephel, Andreas,McConnell, Darryl B.
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p. 10272 - 10293
(2019/11/21)
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- Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A
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A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC50 of 1.0 μM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 (97), a highly potent inhibitor of KAT6A (IC50 = 0.008 μM). WM-8014 competes with acetyl-CoA (Ac-CoA), and X-ray crystallographic analysis demonstrated binding to the Ac-CoA binding site. Through inhibition of KAT6A activity, WM-8014 induces cellular senescence and represents a unique pharmacological tool.
- Leaver, David J.,Cleary, Benjamin,Nguyen, Nghi,Priebbenow, Daniel L.,Lagiakos, H. Rachel,Sanchez, Julie,Xue, Lian,Huang, Fei,Sun, Yuxin,Mujumdar, Prashant,Mudududdla, Ramesh,Varghese, Swapna,Teguh, Silvia,Charman, Susan A.,White, Karen L.,Katneni, Kasiram,Cuellar, Matthew,Strasser, Jessica M.,Dahlin, Jayme L.,Walters, Michael A.,Street, Ian P.,Monahan, Brendon J.,Jarman, Kate E.,Sabroux, Helene Jousset,Falk, Hendrik,Chung, Matthew C.,Hermans, Stefan J.,Parker, Michael W.,Thomas, Tim,Baell, Jonathan B.
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p. 7146 - 7159
(2019/08/28)
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- Direct ortho-Arylation of Pyridinecarboxylic Acids: Overcoming the Deactivating Effect of sp2-Nitrogen
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Direct arylations of pyridines are challenging transformations due to the high Lewis basicity of the sp2-nitrogen. The use of carboxylates as directing groups is reported, facilitating the Pd-catalyzed C-H arylation of this difficult class of substrates. This methodology allows regioselective C3/C4 arylation, without the need to use solvent quantities of the pyridine, and using low-cost chloro- and bromoarenes as coupling partners. Furthermore, carboxylates could be employed as traceless directing groups through a one-pot C-H arylation/Cu(I)-mediated decarboxylation sequence, thereby accessing directing-group-free pyridine biaryls.
- Johnston, Adam J. S.,Ling, Kenneth B.,Sale, David,Lebrasseur, Nathalie,Larrosa, Igor
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supporting information
p. 6094 - 6097
(2016/12/09)
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- NOVEL FAP INHIBITORS
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The present invention relates to novel inhibitors having high selectivity and specificity for FAP (fibroblast activation protein). Said inhibitors are useful as a human and/or veterinary medicine, in particular for the treatment and/or prevention of FAP-related disorders such as but not limited to proliferative disorders.
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Paragraph 0456; 0457; 0458; 0459
(2014/12/09)
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- Extended structure-activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP)
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Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncology applications. We previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, we explore in detail the structure-activity relationship around this core scaffold. We report extensively optimized compounds that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP) the log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo.
- Jansen, Koen,Heirbaut, Leen,Verkerk, Robert,Cheng, Jonathan D.,Joossens, Jurgen,Cos, Paul,Maes, Louis,Lambeir, Anne-Marie,De Meester, Ingrid,Augustyns, Koen,Van Der Veken, Pieter
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supporting information
p. 3053 - 3074
(2014/05/06)
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- NOVEL FAP INHIBITORS
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The present invention relates to novel inhibitors having high selectivity and specificity for FAP (fibroblast activation protein). Said inhibitors are useful as a human and/or veterinary medicine, in particular for the treatment and/or prevention of FAP-related disorders such as but not limited to proliferative disorders.
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Page/Page column 59
(2013/07/31)
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- Synthesis and properties of a dendritic FRET donor-acceptor system with cationic iridium(iii) complex core and carbazolyl periphery
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In order to enhance the photoluminescence of cyclometalated iridium(iii) complexes, which are potentially useful for biolabeling and bioimaging, a series of benzyl ether branched dendritic moieties with carbazolyl termini were introduced to the cyclometal
- Li, Yanfang,Liu, Yang,Zhou, Ming
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experimental part
p. 2582 - 2591
(2012/05/04)
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- CYCLOMETALATED DYE COMPLEXES AND THEIR USE IN DYE-SENSITIZED SOLAR CELLS
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The present invention provides a modular approach to preparing a large array of substituted cyclometalated compounds which behave as dyes having intense absorbance bands in the visible spectrum The compounds include at least one terpyridine-type ligand (tpy) and one cyclometalated tridentate ligand having the bonding motif N,C,N' or C,N, N'. In particular, compounds of formula (I) and formula (II), as shown, where M and R1 to R4 are as defined herein, are disclosed The utility of these compounds in dye-sensitized solar cells (DSSCs) is also taught.
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Page/Page column 34
(2011/04/19)
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- SIRTUIN MODULATING COMPOUNDS
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Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin- modulating compound in combination with another therapeutic agent.
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Page/Page column 74-75
(2009/01/23)
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- ELECTRO LUMINESCENT METAL COMPLEXES
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Electro luminescent metal, e.g. Ir, complexes are disclosed. The metal complexes comprise at least one ligand Ll and at least one ligand L2, wherein ligand Ll is a 2-phenylpyridine ligand (I), comprising a phenyl ring (A) and a pyridine ring (B). The inte
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Page/Page column 24
(2008/06/13)
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- Cyclic derivatives as modulators of chemokine receptor activity
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The present application describes modulators of MCP-1 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the treatment of rheumatoid arthritis, multiple sclerosis, atherosclerosis and asthma.
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Page/Page column 44
(2008/06/13)
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- Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity
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The present application describes modulators of MCP-1 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.
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Page/Page column 43
(2010/02/11)
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