Phosphorus-containing squalene synthetase inhibitors and method

Details Phosphorus-containing squalene synthetase inhibitors and method Phosphorus-containing squalene synthetase inhibitors and method

1993-03-15

1993-12-28

Lee, Mary C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

514 39, 514 54, 558155, 558157, 558158, 562 10, 562 13, A61K 3166, C07F 938, C07F 940

Patent

active

052739694

ABSTRACT:
Compounds which are inhibitors of cholesterol biosynthesis (by inhibiting de novo squalene biosynthesis), and thus are useful as hypocholesterolemic agents and antiatherosclerotic agents are provided which have the structure ##STR1## wherein m is 0, 1, 2 or 3; n is 0, 1, 2, 3 or 4;

REFERENCES:
Poulter, C. D., et al., Biosynthesis of Isoprenoid Compounds, "Conversion of Farnesyl Pyrophosphate to Squalene", vol. 1, Chaper 8, pp. 413-441, J. Wiley and Sons, 1981.
Faust, J. R., et al., Proc. Nat. Acad. Sci., U.S.A., "Squalene synthetase activity in human fibroblasts: Regulation via the low density lipoprotein receptor", 1979, 76, 5018-5022.
de Montellano, P. Ortiz, et al., J. Med. Chem., "Inhibition of Squalene Synthetase by Farnesyl Pyrophosphate Analogues", 1977, 20, 243-249.
Corey and Volante, J. Am. Chem. Soc., "Application of Unreactive Analogs of Terpenoid Pyrophosphates to Studies of Multistep Biosynthesis, Demonstration that `Presqualene Pyrophosphate` is an Essential Intermediate on the Path to Squalene", 1976, 98, 1291-1293.
Sandifer, R. M. et al., J. Am. Chem. Soc., 1982, 104, 7376-7378, "Squalene Synthetase, Inhibition by an Ammonium Analogue of a Carbocationic Intermediate in the Conversion of Presqualene Pyrophosphate to Squalene".
Bertolino, A., et al., Biochim. Biophys. Acta., 1978, 530, 17-23, "Polyisoprenoid Amphiphilic Compounds as Inhibitors of Squalene Synthesis and Other Microsomal Enzymes".
Davisson, V. J. et al., J. Org. Chem., 1986, 51, 4768-4779, "Phosphorylation of Isoprenoid Alcohols".
Stremler, K. E. et al., J.A.C.S., 1987, 109, 5542, "Methane and Difluoromethanediphosphonate Analogues of Geranyl Diphosphate: Hydrolysis-Inert Alternate Substrates".
McClard, R. W., et al., J. Am. Chem. Soc., 1987, 109, 5544-5545, "Novel Phosphonylphosphinyl (P-C-P-C) Analogues of Biochemically Interesting Diphosphates, Syntheses and Properties of P-C-P-C Analogues of Isopentenyl Diphosphate and Dimethylallyl Diphosphate".
Capson, T. L., PhD dissertation, Jun. 1987, Dept. of Medicinal Chemistry, the University of Utah, Abstract, Table of Contents, pp. 16, 17, 40-43, 48-51, Summary.
Stowell, M. H. B., et al., "The Phosphonylphosphinyl Dianion: A Convenient Synthon for the Preparation of Biologically Interesting Phosphonylphosphiny (P-C-P-C) Compounds," Tetrahedron Letters, vol. 30, No. 4, pp. 411-414, 1989.
Biller, S. A. et al., "Isoprenoid (Phosphinylmethyl)phosphonates as Inhibitors of Squalene Synthetase," J. Med. Chem., Oct. 1988, 31, 1869.

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