Biological Diversity from a Structurally Diverse Library: Systematically Scanning Conformational Space Using a Pyranose Scaffold

被引：12

作者：

Abbenante, Giovanni ^{[1
]}

Becker, Bernd ^{[1
]}

Blanc, Sebastien ^{[2
]}

Clark, Chris ^{[1
]}

Condie, Glenn ^{[1
]}

Fraser, Graeme ^{[2
]}

Grathwohl, Matthias ^{[1
]}

Halliday, Judy ^{[1
]}

Henderson, Senka ^{[1
]}

Lam, Ann ^{[1
]}

Liu, Ligong ^{[1
]}

Mann, Maretta ^{[1
]}

Muldoon, Craig ^{[1
]}

Pearson, Andrew ^{[1
]}

Premraj, Rajaratnam ^{[1
]}

Ramsdale, Trade ^{[1
]}

Rossetti, Tony ^{[1
]}

Schafer, Karl ^{[1
]}

Le Thanh, Giang ^{[1
]}

Tometzki, Gerald ^{[1
]}

Vari, Frank ^{[1
]}

Verquin, Geraldine ^{[1
]}

Waanders, Jennifer ^{[1
]}

West, Michael ^{[1
]}

Wimmer, Norbert ^{[1
]}

Yau, Annika ^{[1
]}

Zuegg, Johannes ^{[1
]}

Meutermans, Wim ^{[1
]}

机构：

[1] Alchemia Ltd, Eight Mile Plains, Qld 4113, Australia

[2] Euroscreen SA, B-1070 Brussels, Belgium

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 15期

关键词：

MELANIN-CONCENTRATING HORMONE; BETA-D-GLUCOSE; CARBOHYDRATE-BASED SCAFFOLDS; BINDING AFFINITIES; LEAD OPTIMIZATION; MULTIPLE ROLES; DRUG DESIGN; SOMATOSTATIN; RECEPTOR; ANTAGONISTS;

D O I：

10.1021/jm1002777

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (MCH1) 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.

引用

页码：5576 / 5586

页数：11

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