Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-11-10
1996-04-09
Chan, Nicky
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514422, 514414, 514406, 514397, 514382, 514365, 514338, 514333, 514321, 549363, 549 60, 549 58, 549 28, 549 13, 549310, 548518, 548517, 548468, 548467, 548455, 548454, 548253, 548197, 544377, 544357, 544336, 544335, 544296, 544295, 544238, 544151, 544 61, 544 584, A61K 31335, A61K 31365, C07D40506, C07D31904
Patent
active
055062628
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective but they must be consumed in large quantities, i.e. several grams at a time and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase.
Squalene synthetase is the enzyme involved in the first committed step of the de novo cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA.
Previous efforts at inhibiting squalene synthetase have employed pyrophosphate or pyrophosphate analogs containing compounds such as those described in P. Ortiz de Montellano et al, J. Med Chem. 20, 243 (1977) and E. J. Corey and R. Volante, J. Am. Chem. Soc., 98, 1291 (1976). S. Billet (U.S. Pat. No. 4,871,721) describes isoprenoid (phosphinylmethyl)phosphonates as inhibitors of squalene synthetase.
Recently certain nonphosphorous containing inhibitors of squalene synthetase have been isolated as natural products. These natural product inhibitors are described in European Patent Publications EP 0 448 393 published Sep. 25, 1991, EP 0 450 812 published Oct. 9, 1991, and EP 0 475 706 published Mar. 18, 1992. Application U.S. Ser. No. 07/741,699 filled Aug. 7, 1991, discloses squalene synthetase inhibitors produced by biotransformation of the natural Zaragozic Acid. A need still remains for a more effective squalene synthetase inhibitor, i.e. one that provides a greater antihypercholesterolemic effect and exhibits a good safety profile.
The present invention is directed to semi-synthetic analogs of the above-noted natural products, and the use of these analogs as cholesterol lowering agents.
Also recently it has been disclosed that certain nonphosphorous containing semi-synthetic compounds are inhibitors of squalene synthetase.
Recently it has been shown that certain natural product nonphosphorous containing inhibitors of squalene synthetase and their esters are useful in inhibiting fungal growth. This utility is described in U.S. Pat. No. 5,026,554.
The present invention is also directed to the use of semi-synthetic analogs of the above-noted natural products which are squalene synthetase inhibitors for the inhibition of fungal growth.
The Ras gene is found activated in many human cancers, including colorectal carcinoma, exocrine pancreatic carcinoma, and myeloid leukemias. Biological and biochemical studies of Ras action indicate that Ras functions like a G-regulatory protein, since Ras must be localized in the plasma membrane and must bind with GTP in order to transform cells (Gibbs, J. et al., Microbiol. Rev. 53:171-286 (1989). Forms of Ras in cancer cells have mutations that distinguish the protein from Ras in normal cells.
At least 3 post-translational modifications are involved with Ras membrane localization, and all 3 modifications occur at the C-terminus of Ras. The Ras C-terminus contains a sequence motif termed a "CAAX" or "Cys-Aaa.sup.1 -Aaa.sup.2 -Xaa" box (Aaa is an aliphatic amino acid, the Xaa is any amino acid) (Willumsen et al., Nature 310:583-586 (1984)). Other proteins having this motif include the Ras-related GTP-binding proteins such as Rho, fungal mating factors, the nuclear lamins, and the gamma subunit of transducin.
Farnesylation of Ras by the isoprenoid farnesyl pyrophosphate (FPP) occurs in vivo on Cys to form a thioether linkage (Hancock et al., Cell 57:1167 (1989); Casey et al., Proc. Natl. Acad. Sci. USA 86:8323 (1989)). In addition, Ha-Ras and N-Ras are palmitoylated via formation of a thioester on a Cys residue near a C-terminal Cys fa
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Acton, III John J.
Berger Gregory D.
Bergstrom James D.
Biftu Tesfaye
Bugianesi Robert L.
Chan Nicky
Fitch Catherine D.
Merck & Co. , Inc.
Quagliato Carol S.
Winokur Melvin
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