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Diaminoindanes as Microsomal Triglyceride Transfer Protein Inhibitors

2001; American Chemical Society; Volume: 44; Issue: 26 Linguagem: Inglês

10.1021/jm010294e

1520-4804

Gary M. Ksander, Reynalda deJesus, Andrew Yuan, Cynthia A. Fink, Michael A. Moskal, Eric A. Carlson, Paivi J. Kukkola, Natalie A. Bilci, Eli Wallace, Alan D. Neubert, David N. Feldman, Therese C. Mogelesky, Kevin Poirier, Michael R. Jeune, Ronald E. Steele, Jong Wasvery, Zouhair F. Stephan, Edna Cahill, Randy L. Webb, Aida E. Navarrete, Warren Lee, Joyce Corey Gibson, Natalya Alexander, H. Sharif, Ashok Hospattankar,

Protein Degradation and Inhibitors

The synthesis and biological activities of biarylamide-substituted diaminoindanes as microsomal triglyceride transfer protein (MTP) inhibitors are described. One of the more potent compounds, 8aR, inhibited both the secretion of apoB from Hep G2 cells and the MTP-mediated transfer of triglycerides between synthetic acceptor and donor liposomes with IC(50) values of 0.7 and 70 nM, respectively. In normolipidemic rats and dogs, oral administration of 8aR dose-dependently reduced both plasma triglycerides and total cholesterol. Moreover, in rats and dogs, 8aR also prevented the postprandial rise in plasma triglycerides following a bolus administration of a fat load. Because MTP inhibitors decrease very low density lipoprotein assembly in the liver, the potential for hepatic lipid accumulation was evaluated. In normolipidemic rats, hepatic cholesterol and triglyceride contents were dose-dependently increased by 8aR. However, hepatic lipid accumulation resulted in negligible change in total liver weight and was reversible after withdrawal of the compound.