RG 12561 (dalvastatin): a novel synthetic inhibitor of HMG-CoA reductase and cholesterol-lowering agent.
RG 12561 (dalvastatin) is a prodrug which converts to its open hydroxyacid form in the body. The Na salt of RG 12561 (RG 12561-Na) is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. It competitively inhibits rat liver HMG-CoA reductase with an IC50 value of 3.4 nmol/l. In the same assay, the IC50 values for other potent HMG-CoA reductase inhibitors, lovastatin-Na and pravastatin, were 2.3 and 8.9 nmol/l, respectively. In Hep G2 liver cells, RG 12561-Na, lovastatin-Na and pravastatin inhibited cholesterol biosynthesis from radiolabeled octanoate with IC50 values of 4 and 5 nmol/l and 1.1 mumol/l, respectively. In a rat ex vivo assay, orally administered RG 12561, lovastatin and pravastatin inhibited cholesterol biosynthesis in liver slices with ED50 values of 0.9, 0.5 and 12 mg/kg, respectively. In cholestyramine-fed hamsters, RG 12561 (0.1% in food for 18 days) reduced LDL cholesterol, whereas HDL was slightly increased. The reductions in the LDL/HDL ratio for RG 12561, RG 12561-Na, lovastatin and lovastatin-Na were 35, 76, 88 and 88%, respectively. At a higher dose, RG 12561 (0.4% in food) reduced serum cholesterol, LDL and LDL/HDL by 84, 97 and 91%, respectively. In WHHL rabbits, RG 12561 and lovastatin (5 mg/kg, b.i.d., 12 days) reduced serum cholesterol by 17 and 16%, respectively. These results demonstrate that RG 12561 is a potent cholesterol-lowering agent.
Amin
D
D
Department of Cardiovascular Biology, Rhône-Poulenc Rorer Central Research, Collegeville, Pa. 19426-0107.
Gustafson
S K
SK
Weinacht
J M
JM
Cornell
S A
SA
Neuenschwander
K
K
Kosmider
B
B
Scotese
A C
AC
Regan
J R
JR
Perrone
M H
MH
D000704:Analysis of Variance; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood*; D006224:Cricetinae; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones / Q000494:pharmacology* / Q000627:therapeutic use; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D017035:Pravastatin / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
D000924:Anticholesteremic Agents; D003510:Cyclohexanes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; C071481:dalvastatin; D002784:Cholesterol; D008148:Lovastatin; D017035:Pravastatin