1065331-03-4Relevant 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.
supporting information, (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.
Design of novel aminopyrrolidine factor Xa inhibitors from a screening hit
Zbinden, Katrin Groebke,Anselm, Lilli,Banner, David W.,Benz, Joerg,Blasco, Francesca,Decoret, Guillaume,Himber, Jacques,Kuhn, Bernd,Panday, Narendra,Ricklin, Fabienne,Risch, Philippe,Schlatter, Daniel,Stahl, Martin,Thomi, Stefan,Unger, Robert,Haap, Wolfgang
body text, p. 2787 - 2795 (2009/10/17)
Starting from a hit identified by focused screening, 3-aminopyrrolidine factor Xa inhibitors were designed. The binding mode as determined by X-ray structural analysis as well as the pharmacokinetic behaviour of selected compounds is discussed.
