55240-51-2Relevant articles and documents
Structure-Activity Relationship for the Picolinamide Antibacterials that Selectively Target Clostridioides difficile
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
, p. 991 - 995 (2021/05/27)
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.
Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors
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.
, p. 10272 - 10293 (2019/11/21)
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.
NOVEL FAP INHIBITORS
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Paragraph 0456; 0457; 0458; 0459, (2014/12/09)
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.
