Update on patented cholesterol absorption inhibitors

Expert Opinion on Therapeutic Patents

Volumn 19, Issue 8, 2009, Pages 1083-1107

  Chhabria, M T ^a   Mahajan, B M ^a  

^a L M COLLEGE OF PHARMACY   (India)

Author keywords

ACAT; Atherosclerosis; Bile acid; Cholesterol; Cholesterol absorption inhibitors; Cholesterol esterase; Ezetimibe; Hyperlipidemia; NPC1L1 protein; Phospholipase A2

Indexed keywords

1,4 BIS(4 METHOXYPHENYL) 3 (3 PHENYLPROPYL) 2 AZETIDINONE; 1H INDOLE 3H GLYOXAMIDE; 3 [N (2,2,5,5 TETRAMETHYL 1,3 DIOXANE 4 CARBONYL)AMINO]PROPIONIC ACID 2 (3 NEOPENTYL 3 NONYLUREIDO)CYCLOHEXYL ESTER; A 002; AVASIMIBE; AZETIDINONE DERIVATIVE; BENZOTHIAZEPINE DERIVATIVE; BILE ACID; CHOLESTEROL ACYLTRANSFERASE INHIBITOR; CHOLESTEROL ESTERASE; COLESEVELAM; COLESTIPOL; COLESTYRAMINE; DARAPLADIB; ELDACIMIBE; ENZYME INHIBITOR; EZETIMIBE; EZETIMIBE PLUS SIMVASTATIN; HYPOCHOLESTEROLEMIC AGENT; K 604; KW 3033; OXAZOLIDINONE DERIVATIVE; PACTIMIBE; PHOSPHOLIPASE A2 INHIBITOR; PYRIMIDINONE DERIVATIVE; R 146224; SCH 435495; SCH 53695; SCH 58053; SCH 60663; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ATHEROSCLEROSIS; BINDING AFFINITY; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL METABOLISM; CHRONIC OBSTRUCTIVE LUNG DISEASE; CLINICAL TRIAL; DIARRHEA; DIGESTIVE SYSTEM CANCER; DOSE RESPONSE; DRUG ACTIVITY; DRUG INDUCED HEADACHE; DRUG POTENCY; DRUG SAFETY; DRUG TARGETING; HUMAN; HYPERCHOLESTEROLEMIA; HYPERLIPIDEMIA; IC 50; LIPID ABSORPTION; NAUSEA; NONHUMAN; PATENT; PROSTATE CANCER; REVIEW; SKIN CANCER; STRUCTURE ACTIVITY RELATION;

ABSORPTION; ANIMALS; ANTICHOLESTEREMIC AGENTS; AZETIDINES; BILE ACIDS AND SALTS; BIOLOGICAL TRANSPORT; BLOOD PROTEINS; CHOLESTEROL; HETEROCYCLIC COMPOUNDS; HUMANS; HYPERCHOLESTEROLEMIA; PATENTS AS TOPIC; STEROL ESTERASE; STEROL O-ACYLTRANSFERASE;

EID: 68249102796     PISSN: 13543776     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543770903036826     Document Type: Review

References (114)

1. American heart association statistics committee and stroke subcommittee-2007 update. Dallas, TX: American Heart Association, 2007
2. Lusis AJ. Atherosclerosis. Nature 2000;407:233-241
3. The Expert panel. Summary of the second report of the national cholesterol education program (NCEP) J Am Med Assoc 1993;269:3015-3023
4. Burnett DA. β-Lactam cholesterol absorption inhibitors. Curr Med Chem 2004;11:1873-1887
5. Turley SD, Dietschy JM. Sterol absorption by the small intestine. Curr Opin Lipidol 2003;14:233-240
6. Russell DW. Cholesterol biosynthesis and metabolism. Cardiovasc Drugs Ther 1992;6:103-110
7. Maron DJ, Fazio S, Linton MF. Current perspectives on statins. Circulation 2000;101:207-213
8. Zetia (Ezetimibe). FDA drug approvals 2002 Available from: http://www.fda.gov/cder/foi/label/2006/021445s013lbl.pdf [Last accessed 26 March 2009]
9. Van Heek M, France CF, Compton DS, et al. In vivo mechanism-based discovery of a potent cholesterol absorption inhibitor (SCH-58235) through the identification of the active metabolites of SCH-48461. J Pharmacol Exp Ther 1997;283:157-163
10. Rosenblum SB, Huynh T, Davis HR, et al. Discovery of 1-(4-fluorophenyl)- (3R)-[3-(4-fluorophenyl)- (3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2- azetidinone (SCH-58235): a designed, potent, orally active inhibitor of cholesterol absorption. J Med Chem 1998;41:973-980 (Pubitemid 28146252)
11. Thomas S, Klaus VON. Cholesterol absorption inhibitors for the Treatment of Hypercholesterolaemia. Drugs 2002;62:2333-2347
12. Vytorin (Ezetimibe/Simvastatin). FDA drug approvals. Available from: http://www.fda.gov/cder/foi/label/2004/21687lbl.pdf [Last accessed 26 March 2009]
13. Beisiegel U. Lipoprotein metabolism. Eur Heart J Suppl 1998;19:A20-3
14. Shepherd J. The role of the exogenous pathway in hypercholesterolemia. Eur Heart J Suppl 2001;3:E2-5
15. Russell DW. Cholesterol biosynthesis and metabolism. Cardiovasc Drugs Ther 1992;6:103-110
16. Ikeda I, Matsuoka R, Hamada T, et al. Cholesterol esterase accelerates intestinal cholesterol absorption. Biochim Biophys Acta 2002;1571:34-44 (Pubitemid 34518677)
17. David QH. Regulation of intestinal cholesterol absorption. Annu Rev Physiol 2007;69:221-248
18. Lee RG, Willingham MC, Davis MA, et al. Differential expression of ACAT1 and ACAT2 among cells within liver, intestine, kidney, and adrenal of nonhuman primates. J Lipid Res 2000;4:1991-2001
19. Clader JW. The discovery of ezetimibe: a view from outside the receptor. J Med Chem 2004;47:1-9
20. Clader JW. Substituted (1,2-Diarylethyl) amide Acyl-CoA: cholesterol acyltransferase inhibitors: effect of polar groups on in vitro and in vivo activity. J Med Chem 1995;38:1600-1607
21. Burnett DA, Clader JW, Davis HR. 2-Azetidinones as a inhibitors of cholesterol absorption. J Med Chem 1994;37:1733-1736
22. Clader JW, Burnett DA, Caplen MA. 2-Azetidinone cholesterol absorption inhibitors: structure-activity relationships on the heterocyclic nucleus. J Med Chem 1996;39:3694-3700
23. Dugar S, Kirkup M, Clader JW, et al. Gamma-lactams and related compounds as cholesterol absorption inhibitors: homologs of the beta-lactam cholesterol absorption inhibitor SCH-48461. Bioorg Med Chem Lett 1995;5:2947-2952
24. Bergman M, Morales H, et al. The clinical development of a novel cholesterol absorption inhibitor (abstract). XII International symposium on drugs affecting lipid metabolism 1995;5
25. Van Heek M, Farley C, Compton DS, et al. Comparison of the activity and disposition of the novel cholesterol absorption inhibitor, SCH-58235, and its glucuronide, SCH-60663. Br J Pharmacol 2000;129:1748-1754 (Pubitemid 30219019)
26. Gracia CM, Lisnock J, Bull HG, et al. The target of ezetimibe is Niemann Pick C1-like 1 (NPC1L1). Proc Natl Acad Sci USA 2005;102:8132-8137 (Pubitemid 40800055)
27. Van Heek M, Farley C, Compton DS, et al. Ezetimibe selectively inhibits intestinal cholesterol absorption in rodents in the presence and absence of exocrine pancreatic function. Br J Pharmacol 2001;134:409-417 (Pubitemid 32989139)
28. Van Heek M, Compton DC, Davis HR. The cholesterol absorption inhibitor, ezetimibe, decreases diet-induced hypercholesterolemia in monkeys. Eur J Pharmacol 2001;415:79-84 (Pubitemid 32197622)
29. Harry R, Douglas S, Lizbeth H, et al. Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice. Arterioscler Thromb Vasc Biol 2001;21:2032-2038
30. Catapano AL. Ezetimibe: a selective inhibitor of cholesterol absorption. Eur Heart J Suppl 2001;3:E6-10
31. Seedorf U, Thomas E, Aloys L, et al. Cholesterol absorption inhibitor ezetimibe blocks uptake of oxidized LDL in human macrophages. Biochem Biophys Res Comm 2004;320:1337-1341 (Pubitemid 38916690)
32. Drazen JM, Ware JH, Morrissey S, et al. Ezetimibe and cancer-an uncertain association. N Eng J Med 2008;359:1398-1399
33. Peto R, Emberson J, Landray M, et al. Analysis of cancer data from three ezetimibe trials. N Eng J Med 2008;359:1357-1366
34. Schering Corporation. Spirocycloalkyl-substituted azetidinones useful as hypocholesterolemic agents. WO1994017038; 1994
35. Vaccaro WD, Sher R, Davis HR. 2-Azetidinone cholesterol absorption inhibitors: increased potency by substitution of the C-4 phenyl ring. Bioorg Med Chem 1998;6:1429-1437 (Pubitemid 28446221)
36. Burnett DA, Margaret EB, Clader JW, et al. Synthesis of fluorescent biochemical tools related to the 2-azetidinone class of cholesterol absorption inhibitors. Bioorg Med Chem Lett 2002;12:315-318 (Pubitemid 34113892)
37. Xu B, Xianxiu X, Renzhong F, et al. Ezetimibe analogs with a reorganized azetidinone ring: Design, synthesis, and evaluation of cholesterol absorption inhibitions. Bioorg Med Chem Lett 2007;17:101-104
38. Wang Y, Zhao R, Zhang H, et al. Design and synthesis of 2-azetidinone cholesterol absorption inhibitors. Lett Drug Des Discov 2008;5:39-42 (Pubitemid 351225644)
39. Carreira M, Werder M, Hauser H, et al. Synthesis and in vitro evaluation of inhibitors of intestinal cholesterol absorption. J Med Chem 2005;48:6035-6053 (Pubitemid 41324613)
40. Astrazeneca. Diphenylazetidinone possessing cholesterol absorption inhibitory activity. WO2005061452; 2005
41. Astrazeneca. Diphenylazetidinone possessing cholesterol absorption inhibitory activity. WO2005061451; 2005
42. Astrazeneca. Diphenylazetidinone possessing cholesterol absorption inhibitory activity. US20080064676A1; 2008
43. Schering Corporation. Use of azetidinone compounds. US20070106141; 2007
44. Astrazeneca. New 2-azetidinone derivatives useful in the treatment of hyperlipidaemic conditions. WO2006137792A1; 2006
45. Glombik H, Werner K, Stefanie F, et al. Novel diphenylazetidinones, process for their preparation, medicament comprising these compounds and their use. US20020137689; 2007
46. Sanofi Aventis. Ring substituted azetidinones process for their preparation, medicament comprising these compounds and their use. US7176194; 2007
47. American Home Products Corporation. Tris carbamic acid esters: inhibitors of cholesterol absorption; inhibitors of ACAT and CEH. EP0635501; 1994
48. American Home Products Corporation. 4-Carbamoyloxy-piperidine-1- carboxylic acid esters: inhibitors of cholesterol absorption. AU701447; 1995
49. Pfizer Products. Oxazolidinones as cholesterol absorption inhibitors. WO2008104875A1; 2008
50. Dugar S, Michael PK, Clader JW, et al. Gamma lactams and related compounds as cholesterol absorption inhibitors: homologs of the beta lactam cholesterol absorption inhibitor SCH-48461. Bioorg Med Chem Lett 1995;5:2947-2952
51. Tobias R, Lisbet K, Moritz W, et al. Heterocyclic ring scaffolds as small-molecule cholesterol absorption inhibitors. Org Biomol Chem 2005;3:3514-3523
52. Pfefferkorn JA, Larsen SD, Vanhuis C, et al. Substituted oxazolidinones as novel NPC1L1 ligands for the inhibition of cholesterol absorption. Bioorg Med Chem Lett 2008;18:546-553
53. Vander Jagt DL, Heidrich JE, Linda MC, et al. Inhibition of pancreatic cholesterol esterase reduces cholesterol absorption in the hamster. BMC Pharmacol 2004;4:5-9
54. Feaster SR, Quinn DM. Mechanism-based inhibitors of mammalian cholesterol esterase. Methods Enzymol 1997;286:231-252
55. Feaster SR, Lee K, Baker N, et al. Molecular recognition by cholesterol esterase of active site ligands: structure-activity effects for inhibition by aryl carbamates and subsequent carbamylenzyme turnover. Biochemistry 1996;35:16723-16734 (Pubitemid 27020517)
56. Lin G, Shieh C-T, Tsai YC, et al. Structure-reactivity probes for active site shapes of cholesterol esterase by carbamate inhibitors. Biochim Biophys Acta 1999;1431:500-511 (Pubitemid 29232003)
57. Deck LM, Baca ML, Salas SL, et al. 3-Alkyl-6-chloro-2-pyrones: selective inhibitors of pancreatic cholesterol esterase. J Med Chem 1999;42:4250-4256 (Pubitemid 29483042)
58. Vander Jagt DL, Heynekamp JJ, Hunsaker LA, et al. Isocoumarin-based inhibitors of pancreatic cholesterol esterase. Bioorg Med Chem 2008;16:5285-5294
59. Pietsch M, Gutschow M. Alternate substrate inhibition of cholesterol esterase by thieno[2,3-d][1,3]oxazin-4-ones. J Biol Chem 2002;277:24006-24013
60. Pietsch M, Gutschow M. Synthesis of tricyclic 1,3-oxazin-4-ones and kinetic analysis of cholesterol esterase and acetylcholinesterase inhibition. J Med Chem 2005;48:8270-8288 (Pubitemid 43033318)
61. Schaloske RH, Dennis EA. The phospholipase A2 superfamily and its group numbering. Biochim Biophys Acta 2006;1761:1246-1259
62. Rampone AJ, Machida CM. Mode of action of lecithin in suppressing cholesterol absorption. J Lipid Res 1981;22:744-752 (Pubitemid 11023699)
63. Rampone AJ, Long LR. The effect of phosphatidylcholine and lysophosphatidylcholine on the absorption and mucosal metabolism of oleic acid and cholesterol in vitro. Biochim Biophys Acta 1977;486:500-510
64. Hanasaki K, Yamada K, Yamamoto S, et al. Potent modification of low density lipoprotein by group X secretory phospholipase A2 is linked to macrophage foam cell formation. J Biol Chem 2002;277:29116-29124
65. Kolodgie FD, Burke AP, Skorija KS, et al. Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol 2006;26:2523-2529
66. Warner-Lambert Company. PLA2 inhibitors and their use for inhibition of intestinal cholesterol absorption. US5504073; 1996
67. Smithkline Beecham PLC. 2,5-substituted-1-(aminocarbonylalkyl)-pyrimidin- 4-one derivatives with LpPLA2, inhibitory activity for the treatment of atherosclerosis. WO2003015786; 2003
68. Smith SA, Stansfield IG, Stanway SJ, et al. The discovery of SB-435495: a potent, orally active inhibitor of lipoprotein-associated phospholipase A2 for evaluation in man. Bioorg Med Chem Lett 2002;12:2603-2606
69. Smith SA, Stansfield IG, Stanway SJ, et al. The identification of clinical candidate SB-480848: A potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2003;13:1067-1070
70. Mohler ER, Ballantyne CM, Davidson MH, et al. The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 2008;51:1632-1641
71. Clinical trials of SB-480848. Available from: http://clinicaltrials.gov/ ct2/show/NCT00269048 [Last accessed 26 March 2009]
72. Rosenson RS, Mcconnell D, Elliott M, et al. Effects of 1H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised, placebo-controlled trial. Lancet 2009;373:649-658
73. Corson MA. Phospholipase A2 inhibitors in atherosclerosis: the race is on. Lancet 2009;373:608-610
74. Clinical trials of A-002. Available from: http://clinicaltrials.gov/ct2/ show/NCT00525954?term = A-002&rank = 1 [Last accessed 26 March 2009]
75. Waddah AA, Gill RK. Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm Res 2007;24:1803-1822
76. Kramer W, Buscher HP, Gerok W, et al. Bile salt binding to serum components. Eur J Biochem 1979;102:1-9
77. Kramer W. Identification of the bile acid binding proteins in human serum by photoaffinity labeling. Biochim Biophys Acta 1995;1257:230-238
78. Chiang JYJ. Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms. J Hepatol 2004;40:539-551 (Pubitemid 38230860)
79. Glaxo Wellcome, Inc. Hypolipidemic benzothiazepine compounds. US5859240; 1999
80. Tollefson MB, Vernier WF, Huang H, et al. A novel class of apical sodium co-dependent bile acid transporter inhibitors: the 2,3-disubstituted-4- phenylquinolines. Bioorg Med Chem Lett 2000;10:277-279 (Pubitemid 30105389)
81. Tollefson MB, Stephen AK, Theresa RF, et al. A novel class of apical sodium co-dependent bile acid transporter inhibitors: the 1,2-Benzothiazepines. Bioorg Med Chem Lett 2003;13:3727-3730
82. Tremont SJ, Lee LF, Huang HC, et al. Discovery of potent, nonsystemic apical sodium co-dependent bile acid transporter inhibitors (Part 1). J Med Chem 2005;48:5837-5852 (Pubitemid 41319713)
83. + -dependent bile acid transporter reduces serum cholesterol levels in hamsters and monkeys. Eur J Pharmacol 2006;539:89-98
84. Insull WJ. Clinical utility of bile acid sequestrants in the treatment of dyslipidemia: a specific review. South Med J 2006;99:257-273
85. Davidson MH, Dillon MS, Gordon B, et al. Colesevelam hydrocholoride (cholestragel): a new potent bile acid sequesterants associated with a low incidence of gastrointestinal side effect. Arch Intern Med 1999;159:1893-1900 (Pubitemid 29424709)
86. Clinical trials of colesevelam and ezetimibe combination. Available from: http://clinicaltrials.gov/ct2/show/NCT00185107?term = colesevelam + alone&rank = 4 [Last accessed 26 March 2009]
87. Werner K, Glombik H. Bile acid reabsorption inhibitors (BARI): novel hypolipidemic frugs. Curr Med Chem 2006;13:997-1016
88. Buhman KF, Accad M, Farese RV. Mammalian acyl-CoA:cholesterol acyltransferases. Biochim Biophys Acta 2000;1529:142-154
89. Chang TY, Chang CCY, Cheng D. Acyl-coenzyme A: cholesterol acyltransferase. Annu Rev Biochem 1997;66:613-638
90. Oelkers P, Behari A, Cromley D, et al. Characterization of two human gene encoding acyl coenzyme A- cholesterol acyl transferase related enzymes. J Biol Chem 1998;273:26765-26778 (Pubitemid 28471693)
91. Kushwaha RS, Rosillo A, Roderiguex R, et al. Expression levels of ACAT1 and ACAT2 genes in the liver and intestine of baboons with high and low lipemic responses to dietary lipids. J Nutr Biochem 2005;16:714-721 (Pubitemid 41624793)
92. Akira M, Naomi S, Kiyoshi T, et al. Expression of ACAT-1 protein in human atherosclerotic lesions and cultured human monocytes-macrophages. Arterioscler Thromb Vasc Biol 1998;18:1568-1574 (Pubitemid 28465408)
93. Suckling KE, Stange EF. Role of acyl-CoA cholesterol acyltransferase in cellular cholesterol metabolism. J Lipid Res 1985;26:647-671 (Pubitemid 15248938)
94. American Home Products Corporation. N,N',N'-trisubstituted- 5-bisaminomethylene-1,3-dioxane-4, 6-dione inhibitors of acyl-coa:cholesterol- acyl transferase. US5179216; 1993
95. Kusunoki J, Aragane K, Yamaura T, et al. Studies on acyl-CoA: cholesterol acyltransferase (ACAT) inhibitory effects and enzyme selectivity of F-1394, a pantotheic acid derivative. Jap J Pharmacol 1995;67:195-203
96. Kumazawa T, Yanase M, Shirakura S, et al. Inhibitors of acyl-CoA: cholesterol acyltransferase. II. Preparation and hypocholesterolemic activity of optically active dibenz[b,e]oxepi-11-carboxanilides. Chem Pharm Bull 1996;44:222-225
97. Burnett JR, Huff MW. Avasimibe (Pfizer). Curr Opin Investig Drugs 2002;3:1328-1333
98. Delsing DJM, Offerman EH, Duyvenvoorde W, et al. Acyl-CoA: cholesterol acyltransferase inhibitor avasimibe reduces atherosclerosis in addition to its cholesterol-lowering effect in ApoE*3-leiden mice. Circulation 2001;103:1778-1786 (Pubitemid 32291416)
99. Nissen SE, Tuzcu EM, Brewer HB, et al. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med 2004;354:1253-1263
100. Fazio S, Linton M. Failure of ACAT inhibition to retard atherosclerosis. N Engl J Med 2004;354:1307-1309
101. Terasaka N, Miyazakib A, Kasanuki N, et al. ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice. Atherosclerosis 2007;190:239-247 (Pubitemid 46074038)
102. Clinical trials of pactimibe. Available from: http://clinicaltrials.gov/ ct2/show/NCT00185042?term = pactimibe&rank = 1 [Last accessed 26 March 2009]
103. Ikenoya M, Yoshinaka Y, Kobayashi H, et al. A selective ACAT-1 inhibitor, K-604, suppresses fatty streak lesions in fat-fed hamsters without affecting plasma cholesterol levels. Atherosclerosis 2007;191:290-297 (Pubitemid 46400712)
104. Clinical trials of K-604. Available from: http://clinicaltrials.gov/ct2/ show/NCT00851500?term = K604&rank = 1 [Last accessed 25 February 2009]
105. Takeda Pharmaceutical Company Limited. Coumarin derivative process, process for their production and use thereof. US20070179154; 2007
106. Ikeda I, Tanaka K, Sugano M, et al. Discrimination between cholesterol and sitosterol for absorption in rats. J Lipid Res 1988;29:1583-1591 (Pubitemid 19030526)
107. Davis HR, Zhu LJ, Hoos LM, et al. Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole body cholesterol homeostasis. J Biol Chem 2004;279:33586-33592
108. Berge KE, Tian H, Graf GA, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000;290:1771-1775 (Pubitemid 32004809)
109. Ge L, Wang J, Qi W, et al. The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell Metab 2008;7:508-519 (Pubitemid 351729203)
110. Ling WH, Jones PJ. Dietary phytosterols: a review of metabolism, benefits and side effects. Life Sci 1995;57:195-206
111. Sugano M, Morioka H, Ikeda I. A comparison of hypocholesterolemic activity of beta-sitosterol and beta-sitostanol in rats. J Nutr 1977;107:2011-2019 (Pubitemid 8205901)
112. Burnett J. FM-VP4 (Forbes Medi-Tech). Curr Opin Investig Drugs 2003;4:1120-1125
113. Wasan KM, Najafi S, Wong J, et al. Assessing plasma lipid levels, body weight, and hepatic and renal toxicity following chronic oral administration of water soluble Phytosterol compound, FM-VP4 to gerbils. J Pharm Sci 2001;4:228-234 (Pubitemid 34305598)
114. Wasan KM, Najafi S, Zamfir C, et al. Assessing the plasma pharmacokinetics, tissue distribution, excretion and effects on cholesterol pharmacokinetics of novel hydrophilic compound, FM-VP4, following administration to rats. J Pharm Sci 2001;4:207-216 (Pubitemid 34305596)