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Journal of Pharmacology and Experimental Therapeutics

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OtherCARDIOVASCULAR PHARMACOLOGY

RPR 107393, a Potent Squalene Synthase Inhibitor and Orally Effective Cholesterol-Lowering Agent: Comparison with Inhibitors of HMG-CoA Reductase

Dilip Amin, Ruth Z. Rutledge, Saul N. Needle, Helen F. Galczenski, Kent Neuenschwander, Anthony C. Scotese, Martin P. Maguire, Ray C. Bush, Dave J. Hele, Glenda E. Bilder and Mark H. Perrone
Journal of Pharmacology and Experimental Therapeutics May 1997, 281 (2) 746-752;
Dilip Amin
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Ruth Z. Rutledge
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Saul N. Needle
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Helen F. Galczenski
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Kent Neuenschwander
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Anthony C. Scotese
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Martin P. Maguire
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Ray C. Bush
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Dave J. Hele
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Glenda E. Bilder
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Mark H. Perrone
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Abstract

Squalene synthase catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene and is the first committed step in sterol synthesis. A specific inhibitor of squalene synthase would inhibit cholesterol biosynthesis but not prevent the formation of other products of the isoprenoid pathway, such as dolichol and ubiquinone. RPR 107393 {3-hydroxy-3-[4-(quinolin-6-yl)phenyl]-1-azabicyclo[2-2-2]octane dihydrochloride} and its R and S enantiomers are potent inhibitors of rat liver microsomal squalene synthase, with IC50 values of 0.6 to 0.9 nM. One hour after oral administration to rats, RPR 107393 inhibited de novo[14C]cholesterol biosynthesis from [14C]mevalonate in the liver with an ED50value of 5 mg/kg. Diacid metabolites of [14C]farnesyl pyrophosphate were identified after acid treatment of the livers of these animals. These results support in vitro data demonstrating that these compounds are inhibitors of squalene synthase. In rats, RPR 107393 (30 mg/kg p.o. b.i.d. for 2 days) reduced total serum cholesterol by ≤51%. In the same paradigm, the HMG-CoA reductase inhibitor lovastatin failed to lower serum cholesterol in rats. In marmosets, RPR 107393 (20 mg/kg b.i.d.) reduced plasma cholesterol concentration by 50% after 1 week of administration; this was greater than the reduction observed with lovastatin or pravastatin, neither of which produced > 31% reduction in plasma cholesterol when administered for 1 week at a dose of 50 mg/kg b.i.d. The Rand S enantiomers of RPR 107393 (20 mg/kg p.o. q.d. for 7 days) reduced plasma low density lipoprotein cholesterol by 50% and 43%, respectively, whereas high density lipoprotein cholesterol was unchanged. In summary, RPR 107393 is a potent inhibitor of squalene synthase. It is an orally effective hypocholesterolemic agent in rats and marmosets that has greater efficacy than lovastatin or pravastatin in the marmoset.

Footnotes

  • Send reprint requests to: Dilip Amin, Ph.D., Cardiovascular Biology, Rhône Poulenc Rorer, NW4, 500 Arcola Road, Collegeville, PA 19426-0107.

  • ↵1 R. Bush, unpublished observations.

  • Abbreviations:
    FPP
    farnesyl pyrophosphate
    p.o.
    oral
    s.c.
    subcutaneous
    HDL
    high density lipoprotein
    HPLC
    high pressure liquid chromatography
    LDL
    low density lipoprotein
    VLDL
    very low density lipoprotein
    • Received June 12, 1996.
    • Accepted January 31, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 281, Issue 2
1 May 1997
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OtherCARDIOVASCULAR PHARMACOLOGY

RPR 107393, a Potent Squalene Synthase Inhibitor and Orally Effective Cholesterol-Lowering Agent: Comparison with Inhibitors of HMG-CoA Reductase

Dilip Amin, Ruth Z. Rutledge, Saul N. Needle, Helen F. Galczenski, Kent Neuenschwander, Anthony C. Scotese, Martin P. Maguire, Ray C. Bush, Dave J. Hele, Glenda E. Bilder and Mark H. Perrone
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 746-752;

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OtherCARDIOVASCULAR PHARMACOLOGY

RPR 107393, a Potent Squalene Synthase Inhibitor and Orally Effective Cholesterol-Lowering Agent: Comparison with Inhibitors of HMG-CoA Reductase

Dilip Amin, Ruth Z. Rutledge, Saul N. Needle, Helen F. Galczenski, Kent Neuenschwander, Anthony C. Scotese, Martin P. Maguire, Ray C. Bush, Dave J. Hele, Glenda E. Bilder and Mark H. Perrone
Journal of Pharmacology and Experimental Therapeutics May 1, 1997, 281 (2) 746-752;
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