Design, Synthesis, and Biological Evaluation of α4β1 Integrin Antagonists Based on β-D-Mannose as Rigid Scaffold

✍ Scribed by Jürgen Boer; Dirk Gottschling; Anja Schuster; Bernhard Holzmann; Horst Kessler

• Publisher: John Wiley and Sons
• Year: 2001
• Tongue: English
• Weight: 92 KB
• Volume: 113
• Category: Article
• ISSN: 0044-8249
• DOI: 10.1002/1521-3757(20011015)113:20<3988::aid-ange3988>3.0.co;2-y

✦ Synopsis

The tuning of protein ± protein interactions by small nonpeptidic molecules remains one of the great challenges in medicinal chemistry. Although already proposed in 1980 by Farmer, [1] only a few successful examples on the synthesis of peptidomimetics based on rigid scaffolds such as cyclohexane and pyranose sugars have been reported so far. [2] Starting from the b-d-mannose scaffold we developed peptidomimetics in a rational combinatorial approach focusing on the interaction of the a 4 b 1 and a 4 b 7 integrins with their ligands. The basis of this research were cyclic hexapeptides as potent and selective a 4 b 7 integrin antagonists recently developed by our group using the ªspatial screeningº procedure. [3] a 4 b 1 and a 4 b 7 integrins play an important role in numerous inflammatory and autoimmune disorders. [4] The most important biological ligands for these a 4 integrins are fibronectin reaction mixture was stirred for 6 h. After the solid material had been filtered off, the filtrate was condensed to 5 mL, to which excess diethyl ether was added to obtain the solid product. Slow evaporation of the methanol solution gave crystals of 2 in 81.3 % yield. M.p. 147 8C (decomp).