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A. IntroductionWhen intestinal sucrase and pancreatic a-amylase were identified at Bayer as new targets for improved diabetes therapy (PULS et al. 1973), the problem remained of the best way to find a potent and selective inhibitor of these enzymes. The medicinal chemist today has two alternatives in the search for a first lead compound, firstly the screening of thousands of compounds with maximum structural diversity in a random screening approach, or secondly the rational design of a lead compound, when the biochemical mechanism and the structure of the enzyme are weIl known. In the late 1960s, when we started to look for such potent and selective inhibitors, we had to choose the random screening approach, relying mainly on testing of extracts of the culture broths of microorganisms.Today the mechanism of enzymatic splitting of sucrose by intestinal sucrase is fairly weIl understood. First the glucosidic oxygen atom of sucrose is protonated via a carboxyl group of the enzyme. The splitting of the glucosidic C-O bond is further facilitated by the glucosyl cation being stabilized by a second carboxylate group of the enzyme (COGOLI and SEMENZA 1975). FinaIly, the glucosyl cation reacts with water to give the products 0-glucose and o-fructose. The protonated sucrose molecule land the glucosyl cation 11 are two high-energy intermediates of the enzymatic reaction. Today we know that mimics of such high-energy intermediates are often potent inhibitors of the enzyme. Accordingly, compounds similar in structure to o-glucose but with an easily protonated basic N-atom either in the position of the anomeric oxygen atom (inhibitor type I) or in the position of the ring oxygen atom (inhibitor type 11) should be potent inhibitors of sucrase (Fig. 1). Interestingly, both types of inhibitors represented by either acarbose or I-deoxynojirimycin were found in our random screening. In the foIlowing sections these two types of inhibitors are not discussed in a historical order but under structural criteria. Not included in this discussion are the a-amylase inhibitors of protein nature because there is no evidence that they will find any therapeutic application.

Monosaccharides Containing Nitrogen in the Ring, XXXIX'). Inhibitors of a-L-FucosidaseVariation of the side chain in the 1,3-dithiane derivative 1 of D-galactose leads to a series of analogues of 1,5-dideoxy-1,5-imino-L-fucitol (deoxyfuconojirimycin) (33), which are potent inhibitors of a-L-fucosidase. Cleavage of the dithioacetal in 5 followed by reduction of the aldehyde 6 and deblocking results in 1,5-dideoxy-l,5-imino-~-galactito1 (8). The aldehyde 6 is converted by Wittig reaction to 10 and 14 via 9 and 13, which are homologues of 1,5-dideoxy-l,5-imino-~-fucitol (33). Cyclization of the Wittig product 15 yields the y-lactam 18. After

Amino acids Amino acids U 0400Novel Antifungal β-Amino Acids: Synthesis and Activity Against Candida albicans. -A variety of novel β-amino acids are synthesized and evaluated for their in vitro antifungal activity against Candida albicans. Compound (VIII) appears to be equipotent to cispentacin and exhibits the most favorable activity-tolerability profile among all β-amino acids synthesized so far. Key step in the synthesis of (VIII) is a highly enantioselective, quinine-mediated alcoholysis of the meso-anhydride (V). -(MITTENDORF*, J.; KUNISCH, F.; MATZKE, M.; MILITZER, H.-C.; SCHMIDT, A.; SCHOENFELD, W.; Bioorg. Med. Chem. Lett. 13 (2003) 3, 433-436; Inst. Med.

Five-lipoxygenase (5-LOX) inhibition is gaining increasing importance as a novel approach to therapy of allergic asthma and other inflammatory diseases. Presently, two types of inhibitors are known, direct 5-LOX inhibitors (LOI) and the FLAP (five lipoxygenase activating protein) binding leukotriene synthesis inhibitors (LSI). The 5-LOX selective and orally active quinoline LSI, BAY X 1005, shares many mechanistic features with the indole LSI, MK-886. The binding of BAY X 1005 to FLAP correlates with LTB4 synthesis inhibition. BAY X 1005 has been shown to bind to the 18 kD protein FLAP. BAY X 1005 inhibits 5-LOX translocation from the cytosol to membranes and reverses 5-LOX translocation. The use of BAY X 1005 has helped to elucidate part of the complex FLAP/5-LOX interaction by showing that FLAP appears to represent a 5-LOX substrate transfer protein channelling endogenous and exogenous arachidonic acid to the leukotriene synthetizing 5-LOX. This notion presented by our group in 1992 has stimulated further mechanistic studies. These findings have additionally led to the hypothesis that substrate competition is not confined to the LSI/FLAP interaction but may also be true for the LOI/5-LOX interaction and that even mixed LSI/LOI 5-LOX inhibitors are feasible, yet have not been described. Further mechanistic work on LSI will be orientated not only to further elucidate the complex FLAP/5-LOX interaction, but also to identify FLAP-related eicosanoid binding proteins.