Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE-/- mice by SC-435.
Blocking intestinal bile acid absorption by inhibiting the apical sodium codependent bile acid transporter (ASBT) is a target for increasing hepatic bile acid synthesis and reducing plasma LDL cholesterol. SC-435 was identified as a potent inhibitor of ASBT (IC50 = 1.5 nM) in cells transfected with the human ASBT gene. Dietary administration of 3 mg/kg to 30 mg/kg SC-435 to apolipoprotein E-/- (apoE-/-) mice increased fecal bile acid excretion by >2.5-fold. In vivo inhibition of ASBT also resulted in significant increases of hepatic mRNA levels for cholesterol 7alpha-hydroxylase and HMG-CoA reductase. Administration of 10 mg/kg SC-435 for 12 weeks to apoE-/- mice lowered serum total cholesterol by 35% and reduced aortic root lesion area by 65%. Treatment of apoE-/- mice also resulted in decreased expression of ileal bile acid binding protein and hepatic nuclear hormone receptor small heterodimer partner, direct target genes of the farnesoid X receptor (FXR), suggesting a possible role of FXR in SC-435 modulation of cholesterol homeostasis. In dogs, SC-435 treatment reduced serum total cholesterol levels by </=12% and, in combination with atorvastatin treatment, caused an additional reduction of 25%. These results suggest that specific inhibition of ASBT is a novel therapeutic approach for treatment of hypercholesterolemia resulting in a decreased risk for atherosclerosis.
Bhat
B Ganesh
BG
Cardiovascular and Metabolic Diseases Discovery Research, Pfizer Inc., St. Louis, MO 63167, USA. b.ganesh.bhat@pfizer.com
Rapp
Stephen R
SR
Beaudry
Judith A
JA
Napawan
Nida
N
Butteiger
Dustie N
DN
Hall
Kerri A
KA
Null
Christopher L
CL
Luo
Yi
Y
Keller
Bradley T
BT
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism*; D000069059:Atorvastatin; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017353:Gene Deletion; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology; D027981:Symporters / Q000037:antagonists & inhibitors*; D014326:Tropanes / Q000494:pharmacology*
C466800:1-(4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)butyl)-4-aza-1-azoniabicyclo(2.2.2)octane; D001057:Apolipoproteins E; D001647:Bile Acids and Salts; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D029363:Organic Anion Transporters, Sodium-Dependent; D011758:Pyrroles; D027981:Symporters; D014326:Tropanes; C071908:sodium-bile acid cotransporter; D000069059:Atorvastatin