Bruce David Roth

The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMG-CoA reductase

Abstract The synthesis of CI-981 is described starting from isobutyrylacetanilide ( 3 ) and the key chiral intermediate 2 .

The synthesis of (4R-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for the preparation of CI-981, a highly potent, tissue selective inhibitor of HMG-CoA reductase

Abstract Three alternative methods for the synthesis of the optically active heptanoate ( 6 ), a key intermediate in the preparation of a highly potent and tissue selective HMG Co-A reductase inhibitor are described.

Antiatherosclerotic activity of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cholesterol-fed rabbits: a biochemical and morphological evaluation

Atherosclerotic lesion development was assessed in the thoracic aorta and chronically denuded iliac-femoral artery of hypercholesterolemic New Zealand White rabbits using inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which have previously been shown to possess varying degrees of hepatoselectivity in rats. Atorvastatin, previously known as CI-981 (2.5 mg/kg), PD135022 (1.0 mg/kg), simvastatin (2.5 mg/kg), lovastatin (2.5 mg/kg), PD134965 (1.0 mg/kg), pravastatin (2.5 mg/kg) and BMY22089 (2.5 mg/kg) were added to a 0.5% cholesterol, 3% peanut, 3% coconut oil diet and fed for 8 weeks. Although reductions in plasma total cholesterol of 27% to 60%, VLDL-cholesterol of 31% to 71% and plasma total cholesterol exposure of 37% to 43% were obtained, no correlation between these parameters and vascular lipid content, lesion size or monocyte-macrophage content was noted. Iliac-femoral lipid content was unchanged; however, atorvastatin and simvastatin significantly reduced the cholesterol content of the thoracic aorta by 45%-62%. Atorvastatin and PD135022 reduced the size of the iliac-femoral lesion by 67% and monocyte-macrophage content by 72%. Simvastatin, lovastatin and PD134965 decreased the monocyte-macrophage content; however, lesion size was unchanged. Pravastatin and BMY22089 had no effect on lesion size or content. No compound significantly reduced the extent of thoracic aortic lesions. We concluded that changes in plasma lipids and lipoproteins noted with the various HMG-CoA reductase inhibitors did not account for the beneficial effect on atherosclerotic lesion development. The antiatherosclerotic potential of the HMG-CoA reductase inhibitors was compound-specific and clearly not a class effect.

Hepatic and nonhepatic sterol synthesis and tissue distribution following administration of a liver selective HMG-CoA reductase inhibitor, CI-981 : comparison with selected HMG-CoA reductase inhibitors

Since cholesterol biosynthesis is an integral part of cellular metabolism, several HMG-CoA reductase inhibitors were systematically analyzed in in vitro, ex vivo and in vivo sterol synthesis assays using [14C]acetate incorporation into digitonin precipitable sterols as a marker of cholesterol synthesis. Tissue distribution of radiolabeled CI-981 and lovastatin was also performed. In vitro, CI-981 and PD134967-15 were equipotent in liver, spleen, testis and adrenal, lovastatin was more potent in extrahepatic tissues than liver and BMY21950, pravastatin and PD135023-15 were more potent in liver than peripheral tissues. In ex vivo assays, all inhibitors except lovastatin preferentially inhibited liver sterol synthesis; however, pravastatin and BMY22089 were strikingly less potent in the liver. CI-981 inhibited sterol synthesis in vivo in the liver, spleen and adrenal while not affecting the testis, kidney, muscle and brain. Lovastatin inhibited sterol synthesis to a greater extent than CI-981 in the spleen, adrenal and kidney while pravastatin and BMY22089 primarily affected liver and kidney. The tissue distribution of radiolabeled CI-981 and lovastatin support the changes observed in tissue sterol synthesis. Thus, we conclude that a spectrum of liver selective HMG-CoA reductase inhibitors exist and that categorizing agents as liver selective is highly dependent upon method of analysis.

Synthesis of a chiral synthon for the lactone portion of compactin and mevinolin

Abstract The stereoselective Michael addition of alcohols to 6-tosyloxymethyl-5,6- dihydro-2 H -pyran-2-one afforded high yields of a key chiral synthon for the lactone portion of compactin and mevinolin.

Hep-G2 cells and primary rat hepatocytes differ in their response to inhibitors of HMG-CoA reductase

CI-981, a novel synthetic inhibitor of HMG-CoA reductase, was previously reported to be highly liver-selective using an ex vivo approach. In order to determine liver-selectivity at the cellular level, CI-981 was evaluated in cell culture and compared to lovastatin, pravastatin, fluvastatin and BMY-21950. Using human cell lines, none of the compounds tested showed liver-selectivity, i.e. strong inhibition of cholesterol synthesis in Hep-G2 cells (liver model) but weak inhibition in human fibroblasts (peripheral cell model). In contrast, all drugs tested produced equal and potent inhibition of sterol synthesis in primary cultures of rat hepatocytes, and CI-981, pravastatin and BMY-21950 were more than 100-fold more potent in rat hepatocytes compared to human fibroblasts. Since all compounds were also equally potent at inhibiting sterol synthesis in a rat subcellular system and in vivo, the data suggest that the use of Hep-G2 cells may not be the cell system of choice in which to study inhibition of hepatic cholesterogenesis or to demonstrate liver selectivity of inhibitors of HMG-CoA reductase.

ACAT inhibitors : evolution from cholesterol-absorption inhibitors to antiatherosclerotic agents

Considerable research efforts have focused on the discovery of safe and efficacious acyl-CoA cholesterol acyltransferase (ACAT) inhibitors as cholesterol-lowering and/or antiatherosclerotic agents. Although clinical success remains elusive, recent developments in the molecular biology of ACAT and success in identifying potent and bioavailable inhibitors that are not adrenotoxic has led to renewed hope that ACAT inhibition may ultimately yield agents that will have value in treating human atherosclerotic disease.

Chapter 16. Treatment of Hypercholesterolemia

Publisher Summary This chapter discusses the role of recently appeared inhibitors in the treatment of hypercholesterolemia (HC). The general subject of cholesterol biosynthesis inhibition has been recently reviewed. The indan-1,3-dione causes a 50% inhibition of cytoplasmic S-acetyl coenzyme A synthetase, the enzyme responsible for acetate activation in the first biosynthetic step. Compactin and lovastatin, the first fungal metabolite inhibitors of HMGR, have been the subject of many reviews. Lovastatin has been shown to be the most effective treatment for lowering both TC and LDL-C in patients with primary hypercholesterolemia. A third fungal metabolite under clinical development is pravastatin. Some steroids, bearing a second oxygen function, are known to inhibit HMGR in vitro , possibly by a feedback mechanism. Plant sterols are commonly present in the human diet in edible vegetable oils and fats. The hypocholesterolemic effect of plant sterols, most commonly β-sitosterol, has been well documented in animals and man. Several enzymes have been postulated to be responsible for cholesterol esterification. These are lecithin cholesterol acyl transferase (LCAT), cholesterol esterase (CEH), and acyl cholesterol acyltransferase (ACAT). Pancreatic cholesterol esterase has also been implicated in the esterification of exogenous C. Treatment of HC with bile acid sequestrants remains the first line and most cost effective method of drug therapy. The efficacy of bile-acid sequestrants and HMGR inhibitors, in treating HC in man, is now well documented. Recent research into C absorption inhibitors has uncovered a number of interesting drug types. In the future, increased knowledge of the underlying causes of HC might allow drug therapy to be targeted for specific defects in lipid metabolism.

Inhibitors of Acyl-CoA:Cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents: Synthesis and structure-activity relationships of novel series of sulfonamides, acylphosphonamides and acylphosphoramidates

Sulfoacetic acid, phosphoramidate, and phosphoramide analogs of the ACAT inhibitors, CI-999 and CI-1011 were synthesized. The structure-activity relationships of these compounds as ACAT inhibitors are described.

Imidazolidinones and pyrazolones as novel ACAT inhibitors: Chemistry and biological activity

Abstract Our continued interest in inhibitors of acyl-coenzyme A:cholesterol acyltransferase (ACAT) has led us to study a series of imidazolidinones (I) and a series of pyrazolones (II), two systems structurally distinct from our other reported series. The synthesis and biological activity of I and II are reported.