Eugen Falk

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.

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats

AbstractAim:To investigate the efficacy of the peroxisome proliferator-activated receptor-α (PPARα) agonist, AVE8134, in cellular and experimental models of cardiac dysfunction and heart failure.Methods:In Sprague Dawley rats with permanent ligation of the left coronary artery (post-MI), AVE8134 was compared to the PPARγ agonist rosiglitazone and in a second study to the ACE inhibitor ramipril. In DOCA-salt sensitive rats, efficacy of AVE8134 on cardiac hypertrophy and fibrosis was investigated. Finally, AVE8134 was administered to old spontaneously hypertensive rats (SHR) at a non-blood pressure lowering dose with survival as endpoint. In cellular models, we studied AVE8134 on hypertrophy in rat cardiomyocytes, nitric oxide signaling in human endothelial cells (HUVEC) and LDL-uptake in human MonoMac-6 cells.Results:In post-MI rats, AVE8134 dose-dependently improved cardiac output, myocardial contractility and relaxation and reduced lung and left ventricular weight and fibrosis. In contrast, rosiglitazone exacerbated cardiac dysfunction. Treatment at AVE8134 decreased plasma proBNP and arginine and increased plasma citrulline and urinary NOx/creatinine ratio. In DOCA rats, AVE8134 prevented development of high blood pressure, myocardial hypertrophy and cardiac fibrosis, and ameliorated endothelial dysfunction. Compound treatment increased cardiac protein expression and phosphorylation of eNOS. In old SHR, treatment with a low dose of AVE8134 improved cardiac and vascular function and increased life expectancy without lowering blood pressure. AVE8134 reduced phenylephrine-induced hypertrophy in adult rat cardiomyocytes. In HUVEC, Ser-1177-eNOS phosphorylation but not eNOS expression was increased. In monocytes, AVE8134 increased the expression of CD36 and the macrophage scavenger receptor 1, resulting in enhanced uptake of oxidized LDL.Conclusion:The PPARα agonist AVE8134 prevents post-MI myocardial hypertrophy, fibrosis and cardiac dysfunction. AVE8134 has beneficial effects against hypertension-induced organ damages, resulting in decreased mortality. The compound exerts its protective properties by a direct effect on cardiomyocyte hypertrophy, but also indirectly via monocyte signaling and increased endothelial NO production.