Diaminoindanes as microsomal triglyceride transfer protein 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.
Ksander
G M
GM
Metabolic and Cardiovascular Diseases Research, Novartis Institute for Biomedical Reasearch, Summit, New Jersey 07901, USA. gary.ksander@pharma.novartis.com
deJesus
R
R
Yuan
A
A
Fink
C
C
Moskal
M
M
Carlson
E
E
Kukkola
P
P
Bilci
N
N
Wallace
E
E
Neubert
A
A
Feldman
D
D
Mogelesky
T
T
Poirier
K
K
Jeune
M
M
Steele
R
R
Wasvery
J
J
Stephan
Z
Z
Cahill
E
E
Webb
R
R
Navarrete
A
A
Lee
W
W
Gibson
J
J
Alexander
N
N
Sharif
H
H
Hospattankar
A
A
D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001692:Biological Transport; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002784:Cholesterol / Q000097:blood; D004285:Dogs; D005989:Glycerides / Q000097:blood / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008862:Microsomes, Liver / Q000378:metabolism; D019518:Postprandial Period; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D001713:Biphenyl Compounds
D001055:Apolipoproteins B; D001549:Benzamides; D002352:Carrier Proteins; D002784:Cholesterol; D005989:Glycerides; D000960:Hypolipidemic Agents; D007189:Indans; D007192:Indenes; C443688:(2,3-dihydro-5-(((6-metnyl-4'-(trifluoromethyl)(1,1'-biphenyl)-2-yl)carbonyl)amino)-1H-inden-2-yl)carbamic acid methyl ester; D001713:Biphenyl Compounds