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United States Patent (19) 11 Patent Number: 6,066,653 Gregg Et Al

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United States Patent (19) 11 Patent Number: 6,066,653 Gregg Et Al US006066653A United States Patent (19) 11 Patent Number: 6,066,653 Gregg et al. (45) Date of Patent: May 23, 2000 54 METHOD OF TREATING ACID LIPASE FOREIGN PATENT DOCUMENTS DEFICIENCY DISEASES WITH AN MTP 643057A1 3/1995 European Pat. Off.. INHIBITOR AND CHOLESTEROL WO96/26205 8/1996 WIPO. LOWERING DRUGS OTHER PUBLICATIONS 75 Inventors: Richard E. Gregg, Pennington, N.J.; John R. Wetterau, II, Langhorne, Pa. Scriver et all “The Metabolic and Molecular Bases of Inher ited Disease”, Seventh Edition, vol. II, Chapter 82, "Acid 73 Assignee: Bristol-Myers Squibb Co., Princeton, Lipase Deficiency: Wolman Disease and Cholesteryl Ester N.J. Storage Disease”, pp. 2563–2587, (1995). Scriver et all “The Metabolic and Molecular Bases of Inher 21 Appl. No.: 09/005,437 ited Disease”, Seventh Edition, vol. II, Chapter 85, 22 Filed: Jan. 10, 1998 “Niemann-Pick Disease Type C: A Cellular Cholesterol Lipidosis”, pp. 2625–2639, (1995). Related U.S. Application Data 60 Provisional application No. 60/036,183, Jan. 17, 1997. Primary Examiner Kimberly Jordan 51) Int. Cl." ......................... A61K 3.144s. A61k 3/21 Attorney, Agent, or Firm Burton Rodney; Ronald S. 52 U.S. Cl. ........................... s14/325.514,510,514824. "a" 58 Field of Search ..................................... 514/325, 510, 57 ABSTRACT 514/824 A method is provided for inhibiting- - - - - - - or treating diseases 56) References Cited asSociated with acid lipase deficiency by administering to a patient an MTP inhibitor, alone or optionally, in combination U.S. PATENT DOCUMENTS with another cholesterol lowering drug, Such as pravastatin. 4,346,227 8/1982 Terahara et al. ........................ 560/119 5,712,279 1/1998 Biller et al. ............................. 514/252 27 Claims, No Drawings 6,066,653 1 2 METHOD OF TREATING ACID LIPASE Several species, including humans (2). MTP is composed of DEFICIENCY DISEASES WITH AN MTP two subunits. The small subunit is the previously character INHIBITOR AND CHOLESTEROL ized multifunctional protein, protein disulfide isomerase. LOWERING DRUGS This is supported by biochemical analysis of the protein (3) as well as co-expression Studies performed in insect Sf9 cells using the baculovirus expression System. Expression of This application claims the benefit of U.S. Provisional soluble active MTP requires the co-expression of PDI and Application Ser. No. 60/036,183, filed Jan. 17, 1997. the unique large subunit of MTP (4). FIELD OF THE INVENTION 1: Wetterau, J. R. and Zilversmit, D. B. (1985) Chem. Phys. Lipids 38, 205-222. The present invention related to a method for inhibiting or Wetterau, J. R., et al., (1990) J. Biol. Chem. 265, treating diseases associated with acid lipase deficiency, 98OO-98.07. including Wolman disease and/or cholesteryl ester Storage Wetterau, J. R., et al., (1991) Biochemistry 30, 4406-4412. disease, by administering an MTP inhibitor alone or in Atzel, A., and Wetterau, J. R. (1993) Biochemistry 32, combination with another cholesterol lowering drug, Such as 10444-10450. pravastatin. 15 Atzel, A., and Wetterau, J. R. (1994) Biochemistry 33, 15382-15388. BACKGROUND OF THE INVENTION Jamil, H., et al., (1995) J. Biol. Chem. 270, 6549–6554. 2. Sharp, D. et al., (1993) Nature 365, 65–69. Wolman disease and cholesteryl ester Storage disease are Lin, M. C. M., et al., J. Biol. Chem. 269, 29138-29145. characterized by a deficiency in activity of lysomal acid Nakamuta, M., et al., (1996) Genomics 33, 313–316. lipase which results in massive accumulation of cholesteryl 3. Wetterau, J. R., et al., (1990) J. Biol. Chem. 265, esters and triglycerides in most tissueS of the body. Choles 98OO-98.07. teryl esters and triglycerides are derived from plasma lipo Wetterau, J. R., et al., (1991) Biochemistry 30,9728–9735. proteins taken up by the cells and are Substrates for acid 4. Ricci, B., et al., (1995) J. Biol. Chem. 270, 14281–14285. lipase. Acid lipase is responsible for the hydrolysis of 25 In vitro, MTP catalyzes the transport of lipid molecules cholesteryl esters and triglycerides in the lySOSomes. between phospholipid membranes. Presumably, it plays a If plasma cholesterol levels are lowered sufficiently, then Similar role in Vivo, and thus playS. Some role in lipid cholesteryl ester and triglyceride accumulation in the lyso metabolism. The Subcellular (lumen of the microsomal Somes and the consequences of the accumulation could be fraction) and tissue distribution (liver and intestine) of MTP minimized. have led to speculation that it plays a role in the assembly of Wolman disease is the more severe of the two diseases plasma lipoproteins, as these are the Sites of plasma lipo and is almost always fatal before the age of 1 year. In protein assembly. Wetterau & Zilversmit, Biochem. BiophyS. contrast, cholesteryl ester storage disease may go undetected Acta 875, 610-7 (1986). The ability of MTP to catalyze the until adulthood by which time lipid deposition is wide transport of TG between membranes is consistent with this Spread. Hyperbetalipoproteinemia is common in cholesteryl 35 hypothesis, and Suggests that MTP may catalyze the trans ester Storage disease, and premature atherosclerosis may be port of TG from its site of synthesis in the endoplasmic SCWCC. reticulum (ER) membrane to nascent lipoprotein particles To date, there has been no specific therapy for acid lipase within the lumen of the ER. deficiency other than attempts at Suppression of cholesterol Abetalipoproteinemia is an autosomal recessive disease Synthesis and apolipoprotein B production by 3-hydroxy-3- 40 characterized by a virtual absence of plasma lipoproteins methylglutaryl coenzyme A reductase inhibitors in combi which contain apolipoprotein B (apoB). Kane & Havel in nation with cholestyramine treatment and a diet eXcluding The Metabolic Basis of Inherited Disease, Sixth edition, foods rich in cholesterol and triglycerides. The above appar 1139-64 (1989). Plasma TG levels may be as low as a few ently provided improvement in only one or two cases of mg/dL, and they fail to rise after fat ingestion. Plasma 45 cholesterol levels are often only 20–45 mg/dL. These abnor cholesteryl ester Storage disease. Thus, for the most part, malities are the result of a genetic defect in the assembly Wolman disease and cholesteryl ester Storage disease have and/or secretion of very low density lipoproteins (VLDL) in been untreatable. the liver and chylomicrons in the intestine. The molecular See Scriver, C. R. et all “The Metabolic and Molecular basis for this defect had not been previously determined. In Bases of Inherited Disease”, Vol. II (1995), Chap. 82, “Acid 50 Subjects examined, triglyceride, phospholipid, and choles Lipase Deficiency: Wolman Disease and Cholesteryl Ester terol Synthesis appear normal. At autopsy, Subjects are free Storage Disease”, pp. 2563-2587. of atherosclerosis. Schaefer et al., Clin. Chem. 34, B9-12 Until now, there have not been any therapeutic agents (1988). A link between the apoB gene and abetalipopro available which could lower plasma cholesterol levels suf teinemia has been excluded in Several families. Talmud et ficiently to minimize cholesteryl ester and triglyceride accu 55 al., J. Clin. Invest. 82, 1803-6 (1988) and Huang et al., Am. mulation in the lySOSomes. J. Hum. Genet. 46, 1141-8 (1990). The microsomal triglyceride transfer protein (MTP) cata Recent reports (5) demonstrate that the defect causing lyzes the transport of triglyceride (TG), cholesteryl ester abetalipoproteinemia is in the MTP gene, and as a result, the (CE), and phosphatidylcholine (PC) between small unila MTP protein. When examined, individuals with abetalipo mellar vesicles (SUV). Wetterau & Zilversmit, Chem. Phys. 60 proteinemia have no MTP activity, as a result of mutations Lipids 38,205-22 (1985). When transfer rates are expressed in the MTP gene, some of which have been characterized. as the percent of the donor lipid transferred per time, MTP These results indicate that MTP is required for the synthesis expresses a distinct preference for neutral lipid transport of apoB containing lipoproteins, Such as VLDL, the precur (TG and CE), relative to phospholipid transport. The Sor to LDL. It therefore follows that inhibitors of MTP microSomal triglyceride transfer protein from bovine liver 65 would inhibit the synthesis of VLDL and LDL, thereby has been isolated and extensively characterized (1). This has lowering VLDL levels, LDL levels, cholesterol levels, and led to the cloning of cDNA expressing the protein from triglyceride levels in animals and man. 6,066,653 3 4 5. Wetterau, J. R., et al., (1992) Science 258,999-1001. Patent Application Ser. No. 2,091,102 described hereinbe Sharp, D., et al., (1993) Nature 365, 65–69. fore (corresponding to U.S. application Ser. No. 117,362), Ricci, B., et al., (1995) J. Biol. Chem. 270, 14281–14285. WO 92/26205 published Aug. 29, 1996, U.S. application Shoulders, C. C., et al., (1993) Hum. Mol. Genetics 2, Ser. No. 472,067, filed Jun. 6, 1995 (file DC21e), U.S. 2109-2116. application Ser. No. 548,811, filed Jan. 11, 1996 (file Narcisi, T. M. E., et al., (1995) Am. J. Hum. Genet. 57, DC21h), U.S. provisional application Ser. No. 60/017,224, 1298-1310. filed May 9, 1996 (file HX79a), U.S. provisional applica Rehberg, E. F., et al., J. Biol. Chem (in press). tion Ser. No. 60/017.253, filed May 10, 1996 (file HX82), Canadian Patent Application No. 2,091,102 published U.S. provisional application Ser. No. 60/017,254, filed May Mar. 2, 1994 (corresponding to U.S. application Ser. No. 10, 1996 (file HX84*), and U.S. provisional application Ser. 117,362, filed Sep. 3, 1993 (file DC21b)) which is incorpo No. 60/028.216, filed Oct. 1, 1996 (file HX86*). Preferred rated herein by reference), reports MTP inhibitors which are each of the preferred MTP inhibitors disclosed in each of also block apoB containing lipoprotein Secretion in a human the above applications.
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