Chronic hepatitis B virus (HBV) infection is a major cause of liver disease. Only interferon-alpha and the nucleosidic inhibitors of the viral polymerase, 3TC and adefovir, are approved for therapy. However, these therapies are limited by the side effects of interferon and the substantial resistance of the virus to nucleosidic inhibitors. Potent new antiviral compounds suitable for monotherapy or combination therapy are highly desired. We describe non-nucleosidic inhibitors of HBV nucleocapsid maturation that possess in vitro and in vivo antiviral activity. These inhibitors have potential for future therapeutic regimens to combat chronic HBV infection.

Dedicated to Professor Karl Heinz Biichel on the occasion of his 60th birthday4-Aryl-I ,4-dihydropyridine-3,5-dicarboxylic diesters of the nifedipine type have become almost indispensable for the treatment of cardiovascular diseases since they first appeared on the market in 1975. There are some twenty derivatives currently under clinical development worldwide and work in this area is continuing undiminished. The 1,4-dihydropyridines are the most effective of the calcium antagonists or calcium channel blockers. They are valued not only for their pharmacological effect, but also as a tool for the investigation of the calcium channel, particularly since the discovery that this class also includes compounds that have exactly the opposite action profile and are known as calcium agonists. There are even instances in which this reversal of activity is found between enantiomers. In view of the importance of chirality to pharmacological activity, the present article will describe methods for the separation of enantiomers, point out the structural differences between calcium antagonists and calcium agonists, and attempt to explain the difference in their behavior.

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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.

The inhibition of the cholesteryl ester transfer protein (CETP) provides a method for the elevation of the high density lipoprotein cholesterol (HDL-C) level, i.e. the 'good' cholesterol. The expected anti-atherogenic effect of this approach is independent of the proven benefits of lowering the low density lipoprotein cholesterol (LDL-C) level, i.e. the 'bad' cholesterol. A medicinal chemistry project is presented starting from the first screening hit to the second generation development candidate. The structure-activity relationship, the syntheses and the role of fluorine during optimization, as well as the biological activities are discussed.