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Giovanni Abbenante,
Bernd Becker,
Sébastien Blanc,
Chris Clark,
Glenn Condie,
Graeme Fraser,
Matthias Grathwohl,
Judy Halliday,
Senka Henderson,
Ann Lam, [......],
Giang Le Thanh,
Gerald Tometzki,
Frank Vari,
Géraldine Verquin,
Jennifer Waanders,
Michael West,
Norbert Wimmer,
Annika Yau, Johannes Zuegg,
Wim Meutermans
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ABSTRACT: Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of defined chirality and substitution pattern. A systematic scanning library of 490 compounds was thus designed, produced, and screened in vitro for activity at the somatostatin (sst(1-5)) and melanin-concentrating hormone (MCH(1)) receptors. Bioactive compounds were found for each target, with specific chemoform preferences identified in each case, which can be used to guide follow-on drug discovery projects without the need for scaffold hopping.
Journal of Medicinal Chemistry 08/2010; 53(15):5576-86. · 4.80 Impact Factor
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Giang Le Thanh,
Giovanni Abbenante,
George Adamson,
Bernd Becker,
Chris Clark,
Glenn Condie,
Tania Falzun,
Matthias Grathwohl,
Praveer Gupta,
Michael Hanson, [......],
Sarah Ryan,
Gerry Tometzki,
Geraldine Verquin,
Jennifer Waanders,
Michael West,
Neil Wilcox,
Norbert Wimmer,
Annika Yau, Johannes Zuegg,
Wim Meutermans
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ABSTRACT: The pyranose scaffold is unique in its ability to position pharmacophore substituents in various ways in 3D space, and unique pharmacophore scanning libraries could be envisaged that focus on scanning topography rather than diversity in the type of substituents. Approaches have been described that make use of amine and acid functionalities on the pyranose scaffolds to append substituents, and this has enabled the generation of libraries of significant structural diversity. Our general aim was to generate libraries of pyranose-based drug-like mimetics, where the substituents are held close to the scaffold, in order to obtain molecules with better defined positions for the pharmacophore substituents. Here we describe the development of a versatile synthetic route toward peptide mimetics build on 2-amino pyranose scaffolds. The method allows introduction of a wide range of substituent types, it is regio- and stereospecific, and the later diversity steps are performed on solid phase. Further, the same process was applied on glucose and allose scaffolds, in the exemplified cases, and is likely adaptable to other pyranose building blocks. The methods developed in this work give access to molecules that position the three selected binding elements in various 3D orientations on a pyranose scaffold and have been applied for the production of a systematically diverse library of several hundred monosaccharide-based mimetics.
The Journal of Organic Chemistry 12/2009; 75(1):197-203. · 4.45 Impact Factor
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ChemMedChem 11/2007; 2(10):1403-4. · 3.15 Impact Factor
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ABSTRACT: Monosaccharides provide an excellent platform to tailor molecular diversity by appending desired substituents at selected positions around the sugar scaffold. The presence of five functionalized and stereo-controlled centres on the sugar scaffolds gives the chemist plenty of scope to custom design molecules to a pharmacophore model. This review focuses on the peptidomimetic developments in this area, as well as the concept of tailoring structural and functional diversity in a library using carbohydrate scaffolds and how this can lead to increased hit rates and rapid identification of leads, which has promising prospects for drug development.
Drug Discovery Today 09/2003; 8(15):701-9. · 6.83 Impact Factor
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ABSTRACT: A method of identifying biologically active compounds with defined selectivity profile comprises: (c) designing a library of compounds of formula (1) to scan molecular diversity; and (d) assaying the library of compounds in at least two different biological assays.
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ABSTRACT: A method for inhibiting angiogenesis in a subject comprising administering to the subject at least one compound of General Formula (I), wherein the ring or any chiral center(s) may be of any configuration; Z is sulphur, oxygen, CH2, C(O), C(O)HN, NH, NRA or hydrogen, in the case where Z is hydrogen then R1 is not present, RA is selected from the set defined for R1 to R5, X and X' are independently oxygen or nitrogen providing that at least one X of General Formula (I) is nitrogen, X or X' may also combine independently with one of R1 to R5 to form an azide, R1 to R5 are independently selected from the following definition which includes but is not limited to H or an alkyl, acyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituent of 1 to 20 atoms, which is optionally substituted, and can be branched or linear, and R6 and R7 are hydrogen, or may combine to form a carbonyl function.
