- Design and Synthesis of 56 Shape-Diverse 3D Fragments
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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.
- 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.
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supporting information
(2020/07/13)
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- PYRAZOLO[4,3-D]PYRIMIDIN-7(6H)-ONE DERIVATIVES AS PDE9 INHIBITORS
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Pyrazolo[4,3-d]pyrimidin-7(6H)-one derivatives represented by the general formula (I), wherein R1 represents hydrogen atom or methyl; when R1 represents hydrogen atom, then R2 represents cyclopentyl, tetrahydropyranyl, cyclohexyl, or cyclohexyl substituted with 1 or 2 halogen atoms; when R1 represents methyl, then R2 represents cyclopentyl; R3 is selected from the group consisting of phenyl unsubstituted or substituted with 1 to 3 substituents selected from F, Cl, Br, I, and OCH3; and 6- to 10-membered heteroaryl with 1 to 3 heteroatoms selected independently form O, N and S; and Q represents C1-C3-alkylene group, which is unsubstituted or substituted with 1 to 3 C1-C3-alkyl groups; and their salts. The compounds are PDE9A inhibitors useful as m edicaments, in particular for treatment of cognitive function disorders and neurodegenerative diseases
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- Design of novel aminopyrrolidine factor Xa inhibitors from a screening hit
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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.
- 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
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body text
p. 2787 - 2795
(2009/10/17)
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