888952-55-4Relevant articles and documents
Design and Synthesis of 56 Shape-Diverse 3D Fragments
Atobe, Masakazu,Blakemore, David C.,Bond, Paul S.,Chan, Ngai S.,De Fusco, Claudia,Downes, Thomas D.,Firth, James D.,Hubbard, Roderick E.,Jones, S. Paul,Klein, Hanna F.,O'Brien, Peter,Roughley, Stephen D.,Vidler, Lewis R.,Waddelove, Laura,Whatton, Maria Ann,Wheldon, Mary C.,Woolford, Alison J.-A.,Wrigley, Gail L.
, (2020/07/13)
Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol?1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity.
Identification of novel TACE inhibitors compatible with topical application
Ouvry, Gilles,Berton, Ya?l,Bhurruth-Alcor, Yushma,Bonnary, Laetitia,Bouix-Peter, Claire,Bouquet, Karine,Bourotte, Marilyne,Chambon, Sandrine,Comino, Catherine,Deprez, Beno?t,Duvert, Denis,Duvert, Gwena?lle,Hacini-Rachinel, Feriel,Harris, Craig S.,Luzy, Anne-Pascale,Mathieu, Arnaud,Millois, Corinne,Pascau, Jonathan,Pinto, Artur,Polge, Ga?lle,Reitz, Arnaud,Reversé, Kevin,Rosignoli, Carine,Taquet, Nathalie,Hennequin, Laurent F.
, p. 1848 - 1853 (2017/04/04)
Targeting the Tumor Necrosis Factor α signalling with antibodies has led to a revolution in the treatment of psoriasis. Locally inhibiting Tumor Necrosis Factor α Converting Enzyme (TACE or ADAM17) could potentially mimic those effects and help treat mild to moderate psoriasis, without the reported side effect of systemic TACE inhibitors. Efforts to identify new TACE inhibitors are presented here. Enzymatic SAR as well as ADME and physico-chemistry data are presented. This study culminated in the identification of potent enzymatic inhibitors. Suboptimal cellular activity of this series is discussed in the context of previously published results.
BENZAMIDE IMIDAZOPYRAZINE BTK INHIBITORS
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Page/Page column 66; 67, (2016/07/27)
Provided are Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula I, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, or their use in therapy.
