Because of their high selectivity against other serine proteases, for example thrombin, trypsin, or factor Xa, the development of bifunctional tryptase inhibitors has attracted much attention during recent years. Several classes of effective dibasic tryptase inhibitor have been reported, recently [13, 14, 23]. Herein, we describe syn-

Fig. 3.2.1. Crystal structure of tetrameric j-tryptase, consisting of monomers A, B, C, and D, with a symbolized bifunctional inhibitor interacting with two active sites simultaneously. The distances between neighboring active centers are @20A and @40A (A-D and A-B) [16].

theses of two generations of dibasic tryptase inhibitor, including structure-activity relationships (SAR) and typical selectivity data. Initially, target inhibitors containing pyran rings as central scaffolds (Scheme 3.2.1, 1 and 2), derived from tri-O-acetyl glucal 10, were created, leading to more polar compounds of type I. With the introduction of aryl diynes as central templates (Scheme 3.2.1, 3 [24], 4 [25], 5 [26],

Fig. 3.2.2. Two monofunctional tryptase inhibitors for inhalative application - APC 366 (Axys Pharmaceuticals) and BABIM.

3.2.2 Chemistry I 231


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