Gunther Wess

Bile acids in drug discovery

Abstract Recent advances have provided important new information on the physiological mechanisms of bile acid transport and metabolism. Bile acids, which are essential for the digestion and absorption of lipids and lipid-soluble vitamins, are metabolic products of cholesterol and are a major regulator of cholesterol homeostasis. Bile acids are pharmacologically interesting as potential carriers of liver-specific drugs, absorption enhancers and as new cholesterol-lowering agents. Furthermore, the tools of molecular recognition and combinatorial chemistry have been used to explore the drug discovery possibilities of bile acids. The authors explore current understanding and future prospects for bile acid research.

Bile acid transport systems as pharmaceutical targets

Drug targeting aims to improve the therapeutic index of a drug, i.e. to maximize the ratio between the desired pharmacological action and adverse sideeffects. This requires the achievement of a high drug concentration in the target organ of the body. As direct application of the drug to the target organ is rare, the drug has to be administered systemically. For chronic diseases requiring long-term or lifetime treatment, non-invasive drug application is necessary. Specific problems with peptide and protein drugs are their low permeability through biological membranes, their negligible intestinal absorption and their susceptibility to enzymatic hydrolysis. Drug targeting implies, at a molecular level, specific recognition and uptake of the drug by the target tissue, and thus three molecular characteristics are important for drug delivery: the drug molecule, the drug carrier; and the molecular recognition signals. Ideally, all three factors are combined in a small drug molecule [1-3], but in most cases the drug carrier should mediate specific recognition at the target cells. The liver occupies a central role in the metabolism of drugs, and many pathological states are unique to this organ, such as liver infections (hepatitis, malaria, leishmaniasis, etc.), lipid disorders, cirrhosis, metabolic disorders, storage disease or hepatobiliary carcinomas. None of these diseases can be treated satisfactorily by current pharmacological drugs, because of either lack of active drugs or limitations due to adverse side-effects in extrahepatic tissues. It is essential that drugs used to treat these diseases should be liver specific. Many drugs by themselves reach relatively high concentrations in the liver as a result of a high first-pass effect.

Bile acid derived HMG-CoA reductase inhibitors

The target organ for HMG-CoA reductase inhibitors to decrease cholesterol biosynthesis in hypercholesterolemic patients is the liver. Since bile acids undergo an enterohepatic circulation showing a strict organotropism for the liver and the small intestine, the structural elements of an inhibitor for HMG-CoA reductase were combined with those for specific molecular recognition of a bile acid molecule for selective uptake by hepatocytes. Either, the HMG-CoA reductase inhibitors HR 780 and mevinolin were covalently attached to 3 xi-(omega-aminoalkoxy)-7 alpha, 12 alpha-dihydroxy-5 beta-cholan-24-oic acids to obtain bile acid prodrugs, or the side chain of bile acids at C-17 was replaced by 3,5-dihydroxy-heptanoic acid--a structural element essential for inhibition of HMG-CoA reductase--to obtain hybrid bile acid: HMG-CoA reductase inhibitors. The prodrugs could, as expected, not inhibit rat liver HMG-CoA reductase to a significant extent, whereas the hybrid inhibitors showed a stereospecific inhibition of HMG-CoA reductase from rat liver microsomes with an IC50-value of 0.7 microM for the most potent compound S 2467 and 6 microM for its diastereomere S 2468. Uptake measurements with isolated rat hepatocytes and ileal brush-border membrane vesicles from rabbit small intestine revealed a specific interaction of both classes of bile acid-derived HMG-CoA reductase inhibitors with the hepatocyte and ileocyte bile acid uptake systems. Photoaffinity labeling studies using 3-azi- or 7-azi-derivatives of taurocholate with freshly isolated rat hepatocytes or rabbit ileal brush-border membrane vesicles revealed a specific interaction of bile acid derived HMG-CoA reductase inhibitors with the respective putative bile acid transporters in the liver and the ileum demonstrating the bile acid character of these derivatives, both for the prodrugs and the hybrids. Cholesterol biosynthesis in Hep G2 cells was inhibited by the bile acid prodrugs with IC50-values in the range of 68 nM to 600 nM compared to 13 nM for HR 780 and 130 nM for mevinolin. Among the hybrid inhibitors, S 2467 was the most active compound with an IC50-value of 16 microM compared to 55 microM for its diastereomere S 2468. Preliminary in vivo experiments showed an inhibition of hepatic cholesterol biosynthesis after oral dosage only with prodrugs such as S 3554, whereas the hybrid molecules were inactive after oral application.(ABSTRACT TRUNCATED AT 400 WORDS)

Modified bile acids as carriers for peptides and drugs

Abstract For the development of future drugs two aspects are of major importance, a site-specific drug action without adverse side-effects and a preferably oral applicability. The liver has a central role in drug action and many disorders are unique to the liver demanding a liver-specific drug action. In oral drug therapy the small intestine is often the limiting barrier of drug absorption. Bile acids are natural substrates undergoing an enterohepatic circulation involving the liver and the small intestine. This organotropism of bile acids is achieved by specific Na + -dependent transport systems in the plasma membrane of hepatocytes and ileocytes. Di- and tripeptides as well as orally active α -amino- β -lactam antibiotics are intestinally absorbed by a H + /oligopeptide cotransport system of high transport capacity. We, therefore, investigated whether the hepatic and the intestinal bile acid transport systems as well as the intestinal H + /oligopeptide transporter can be used in drug therapy to improve the membrane permeability and intestinal absorption of peptide drugs, to target a drug to the liver and the biliary system and to obtain liver-specific drugs. For this, modified bile acids with linkers of varying structure, length, position and stereochemistry at the steroid nucleus were synthesized and covalently linked to drugs or peptides or alternatively bile acid structural elements were introduced into drugs. To investigate the H + /oligopeptide transporter as a putative peptide delivery system, peptides were covalently attached to the 3′-position of the tripeptide-analogue d -cephalexin. The interaction of these bile acid and cephalexin conjugates with the hepatic and intestinal bile acid and peptide transport systems as well as their pharmacokinetic and pharmacodynamic behaviour was investigated by transport measurements and photoaffinity labeling techniques using membrane vesicles, isolated hepatocytes and in vivo models.

Editorial: Dissecting G‐Protein‐Coupled Receptors: Structure, Function, and Ligand Interaction

In January 2001, the University of Frankfurt and Aventis started a series of workshops – as part of the companys [i]lab initiative. The aim of these workshops is to stimulate discussions in the field of chemical biology between scientists, students, and postdoctoral fellows, both from academia and from industry. The first workshop focused on G-proteincoupled receptors (GPCRs), and this issue of ChemBioChem is dedicated to contributions primarily presented at the workshop dealing with this important class of membrane proteins. During this workshop, the discussion about GPCRs, covering a variety of different scientific approaches, created an intense atmosphere of exchange of concepts and ideas. Similarly, we believe that this special edition of ChemBioChem, by bringing together contributions about the structure, function, and ligand interaction of GPCRs will provide new insight and stimulate the development of novel scientific approaches.

Challenges for medicinal chemistry

Medicinal chemistry has become the most time-consuming step in the drug discovery process, and new discovery technologies are likely to increase the burden on lead optimization and refinement. Although medicinal chemists are able to optimize hits/leads very quickly and successfully with regard to potency, improving the kinetic, metabolic and toxicological properties of a compound remains a difficult challenge. The author examines the role of the medicinal chemist in this increasingly complex and changing environment.