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• W2030031111 abstract "A microsomal triglyceride transfer protein (MTP) inhibitor, CP-346086, was identified that inhibited both human and rodent MTP activity [concentration giving half-maximal inhibition (IC50) 2.0 nM]. In Hep-G2 cells, CP-346086 inhibited apolipoprotein B (apoB) and triglyceride secretion (IC50 2.6 nM) without affecting apoA-I secretion or lipid synthesis. When administered orally to rats or mice, CP-346086 lowered plasma triglycerides [dose giving 30% triglyceride lowering (ED30) 1.3 mg/kg] 2 h after a single dose. Coadministration with Tyloxapol demonstrated that triglyceride lowering was due to inhibition of hepatic and intestinal triglyceride secretion. A 2 week treatment with CP-346086 lowered total, VLDL, and LDL cholesterol and triglycerides dose dependently with 23%, 33%, 75%, and 62% reductions at 10 mg/kg/day. In these animals, MTP inhibition resulted in increased liver and intestinal triglycerides when CP-346086 was administered with food. When dosed away from meals, however, only hepatic triglycerides were increased. When administered as a single oral dose to healthy human volunteers, CP-346086 reduced plasma triglycerides and VLDL cholesterol dose dependently with ED50s of 10 mg and 3 mg, and maximal inhibition (100 mg) of 66% and 87% when measured 4 h after treatment. After a 2 week treatment (30 mg/day), CP-346086 reduced total and LDL cholesterol and triglycerides by 47%, 72%, and 75%, relative to either individual baselines or placebo, with little change in HDL cholesterol.Together, these data support further evaluation of CP-346086 in hyperlipidemia. A microsomal triglyceride transfer protein (MTP) inhibitor, CP-346086, was identified that inhibited both human and rodent MTP activity [concentration giving half-maximal inhibition (IC50) 2.0 nM]. In Hep-G2 cells, CP-346086 inhibited apolipoprotein B (apoB) and triglyceride secretion (IC50 2.6 nM) without affecting apoA-I secretion or lipid synthesis. When administered orally to rats or mice, CP-346086 lowered plasma triglycerides [dose giving 30% triglyceride lowering (ED30) 1.3 mg/kg] 2 h after a single dose. Coadministration with Tyloxapol demonstrated that triglyceride lowering was due to inhibition of hepatic and intestinal triglyceride secretion. A 2 week treatment with CP-346086 lowered total, VLDL, and LDL cholesterol and triglycerides dose dependently with 23%, 33%, 75%, and 62% reductions at 10 mg/kg/day. In these animals, MTP inhibition resulted in increased liver and intestinal triglycerides when CP-346086 was administered with food. When dosed away from meals, however, only hepatic triglycerides were increased. When administered as a single oral dose to healthy human volunteers, CP-346086 reduced plasma triglycerides and VLDL cholesterol dose dependently with ED50s of 10 mg and 3 mg, and maximal inhibition (100 mg) of 66% and 87% when measured 4 h after treatment. After a 2 week treatment (30 mg/day), CP-346086 reduced total and LDL cholesterol and triglycerides by 47%, 72%, and 75%, relative to either individual baselines or placebo, with little change in HDL cholesterol. Together, these data support further evaluation of CP-346086 in hyperlipidemia. Cardiovascular disease remains the leading cause of death in industrialized nations and accounted for 950,000, or 41%, of all deaths in the United States in 1998 (1American Heart Association 2001 Heart and Stroke Statistical Update. American Heart Association, Dallas, TX2001Google Scholar). As a consequence of atherosclerosis, coronary heart disease (CHD) is the most common cause of cardiovascular morbidity and mortality, with an estimated 12 million people suffering from CHD in the United States alone (1American Heart Association 2001 Heart and Stroke Statistical Update. American Heart Association, Dallas, TX2001Google Scholar). Elevated total and LDL cholesterol are both accepted primary risk factors for atherosclerosis (1American Heart Association 2001 Heart and Stroke Statistical Update. American Heart Association, Dallas, TX2001Google Scholar, 2International Lipid Information Bureau The ILIB Lipid Handbook for Clinical Practice. Blood Lipids and Coronary Heart Disease. International Lipid Information Bureau, Morris Plains, NJ1995Google Scholar, 3National Cholesterol Education Program Expert Panel Second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults; Adult Treatment Panel II.Circulation. 1994; 89: 1329-1445Google Scholar). An estimated 101 million United States adults have elevated blood cholesterol (>200 mg/dl) and are candidates for LDL cholesterol lowering through dietary intervention (1American Heart Association 2001 Heart and Stroke Statistical Update. American Heart Association, Dallas, TX2001Google Scholar, 4Sempos C.T. Cleeman J.I. Carroll M.D. Johnson C.L. Bachorik P.S. Gordon D.J. Burt V.L. Briefel R.R. Brown C.D. Lippel K. Rifkind B.M. Prevalence of high blood cholesterol among US adults. An update on guidelines from the second report of the National Cholesterol Education Program Adult Treatment Panel.J. Am. Med. Assoc. 1993; 269: 3009-3014Google Scholar, 5Bays H.E. Dujovne C.A. Lansing A.M. Drug treatment of dyslipidemias: practical guidelines for the primary care physician.Heart Dis. Stroke. 1992; 1: 357-365Google Scholar). Of these, 41 million are considered high risk, having blood cholesterol greater than 240 mg/dl, and drug therapy is recommended (1American Heart Association 2001 Heart and Stroke Statistical Update. American Heart Association, Dallas, TX2001Google Scholar, 4Sempos C.T. Cleeman J.I. Carroll M.D. Johnson C.L. Bachorik P.S. Gordon D.J. Burt V.L. Briefel R.R. Brown C.D. Lippel K. Rifkind B.M. Prevalence of high blood cholesterol among US adults. An update on guidelines from the second report of the National Cholesterol Education Program Adult Treatment Panel.J. Am. Med. Assoc. 1993; 269: 3009-3014Google Scholar, 5Bays H.E. Dujovne C.A. Lansing A.M. Drug treatment of dyslipidemias: practical guidelines for the primary care physician.Heart Dis. Stroke. 1992; 1: 357-365Google Scholar). Epidemiological studies have shown that elevated triglycerides and reduced HDL cholesterol are also contributing factors for the development of CHD (2International Lipid Information Bureau The ILIB Lipid Handbook for Clinical Practice. Blood Lipids and Coronary Heart Disease. International Lipid Information Bureau, Morris Plains, NJ1995Google Scholar, 3National Cholesterol Education Program Expert Panel Second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults; Adult Treatment Panel II.Circulation. 1994; 89: 1329-1445Google Scholar, 6Patsch W. Gotto Jr., A.M. High-density lipoprotein cholesterol, plasma triglyceride, and coronary heart disease: pathophysiology and management.Adv. Pharmacol. 1995; 32: 375-426Google Scholar, 7Vega G.L. Grundy S.M. Hypoalphalipoproteinemia (low high density lipoprotein) as a risk factor for coronary heart disease.Curr. Opin. Lipidol. 1996; 7: 209-216Google Scholar, 8Wilt V.M. Gums J.G. Isolated low high-density lipoprotein cholesterol.Ann. Pharmacother. 1997; 31: 89-97Google Scholar). Among the adult United States population, 19% of people have low HDL cholesterol (<40 mg/dl) (3National Cholesterol Education Program Expert Panel Second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults; Adult Treatment Panel II.Circulation. 1994; 89: 1329-1445Google Scholar, 9Rubins H.B. Robins S.J. Collins D. The veterans affairs high-density lipoprotein intervention trial: baseline characteristics of normocholesterolemic men with coronary artery disease and low levels of high-density lipoprotein cholesterol.Am. J. Cardiol. 1996; 78: 572-575Google Scholar, 10National Cholesterol Education Program Expert Panel Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).J. Am. Med. Assoc. 2001; 285: 2486-2497Google Scholar) and 21% have hypertriglyceridemia (>150 mg/dl) (3National Cholesterol Education Program Expert Panel Second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults; Adult Treatment Panel II.Circulation. 1994; 89: 1329-1445Google Scholar, 10National Cholesterol Education Program Expert Panel Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).J. Am. Med. Assoc. 2001; 285: 2486-2497Google Scholar). Thus, as important as elevated LDL cholesterol is as a risk factor for CHD, it is important to recognize that the most common spectrum of lipid abnormalities is atherogenic dyslipidemia, which is present in 45–50% of men with CHD (11Superko H.R. The atherogenic lipoprotein profile.Sci. Med. 1997; 4: 36-45Google Scholar, 12Grundy S.M. Small LDL, atherogenic dyslipidemia, and the metabolic syndrome.Circulation. 1997; 95: 1-4Google Scholar) and includes borderline high-risk LDL cholesterol (e.g., 130–159 mg/dl), elevated triglycerides, small dense LDL particles, and low HDL cholesterol. The HMG-CoA reductase inhibitors (statins) are very effective in lowering LDL cholesterol and somewhat effective in reducing triglycerides, but they have only minimal effects on HDL cholesterol (2International Lipid Information Bureau The ILIB Lipid Handbook for Clinical Practice. Blood Lipids and Coronary Heart Disease. International Lipid Information Bureau, Morris Plains, NJ1995Google Scholar, 5Bays H.E. Dujovne C.A. Lansing A.M. Drug treatment of dyslipidemias: practical guidelines for the primary care physician.Heart Dis. Stroke. 1992; 1: 357-365Google Scholar, 13Scandinavian Simvastatin Survival Study Group Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S).Lancet. 1994; 344: 1383-1389Google Scholar, 14Shepherd J. Cobbe S.M. Ford I. Isles C.G. Lorimer A.R. MacFarlane P.W. McKillop J.H. Packard C.J. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.N. Engl. J. Med. 1995; 333: 1301-1307Google Scholar, 15Sacks F.M. Pfeffer M.A. Moye L.A. Rouleau J.L. Rutherford J.D. Cole T.G. Brown L. Warnica J.W. Arnold J.M.O. Wun C.C. Davis B.R. Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.N. Engl. J. Med. 1996; 335: 1001-1009Google Scholar). Indeed, although numerous clinical trials have demonstrated that LDL cholesterol reduction can significantly reduce CHD risk, a great number of treated subjects who achieve substantial LDL cholesterol reduction still experience a clinical event (2International Lipid Information Bureau The ILIB Lipid Handbook for Clinical Practice. Blood Lipids and Coronary Heart Disease. International Lipid Information Bureau, Morris Plains, NJ1995Google Scholar, 3National Cholesterol Education Program Expert Panel Second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults; Adult Treatment Panel II.Circulation. 1994; 89: 1329-1445Google Scholar, 13Scandinavian Simvastatin Survival Study Group Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S).Lancet. 1994; 344: 1383-1389Google Scholar, 14Shepherd J. Cobbe S.M. Ford I. Isles C.G. Lorimer A.R. MacFarlane P.W. McKillop J.H. Packard C.J. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.N. Engl. J. Med. 1995; 333: 1301-1307Google Scholar, 15Sacks F.M. Pfeffer M.A. Moye L.A. Rouleau J.L. Rutherford J.D. Cole T.G. Brown L. Warnica J.W. Arnold J.M.O. Wun C.C. Davis B.R. Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.N. Engl. J. Med. 1996; 335: 1001-1009Google Scholar, 16Lipid Research Clinics Program The lipid research clinics coronary primary prevention trial results: I. Reduction in incidence of coronary heart disease. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering.J. Am. Med. Assoc. 1984; 251: 351-374Google Scholar, 17Blankenhorn D.H. Nessim S.A. Johnson R.L. Sanmarco M.E. Azen S.P. Cashin-Hemphill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts.J. Am. Med. Assoc. 1987; 257: 3233-3240Google Scholar, 18Coronary Drug Project Research Group Clofibrate and niacin in coronary heart disease.J. Am. Med. Assoc. 1975; 231: 360-381Google Scholar). Therefore, with the goal of developing a therapy for treating patients with dyslipidemias that extend beyond primary hypercholesterolemia, we targeted inhibition of microsomal triglyceride transfer protein (MTP) as a mechanism for preventing triglyceride-rich lipoprotein assembly in the liver and intestine. MTP, which is located within the lumen of the endoplasmic reticulum (ER) in hepatocytes and absorptive enterocytes, is a heterodimeric protein consisting of a 97 kDa subunit, which confers all of the lipid transfer activity of the heterodimer, and the 58 kDa multifunctional protein disulfide isomerase (19Wetterau J.R. Lin M.C.M. Jamil H. Microsomal triglyceride transfer protein.Biochim. Biophys. Acta. 1977; 1345: 136-150Google Scholar). MTP plays a pivotal, if not obligatory role, in the assembly and secretion of triglyceride-rich, apolipoprotein B (apoB)-containing lipoproteins (VLDL and chylomicrons) from the liver and intestine and also catalyzes the transport of triglycerides, cholesteryl esters, and phospholipids between membranes (19Wetterau J.R. Lin M.C.M. Jamil H. Microsomal triglyceride transfer protein.Biochim. Biophys. Acta. 1977; 1345: 136-150Google Scholar, 20Gordon D.A. Wetterau J.R. Gregg R.E. Microsomal triglyceride transfer protein: a protein complex required for the assembly of lipoprotein particles.Trends Cell Biol. 1995; 5: 317-321Google Scholar, 21Olofsson S.O. Asp L. Boren J. The assembly and secretion of apolipoprotein B-containing lipoproteins.Curr. Opin. Lipidol. 1999; 10: 341-346Google Scholar). Although the exact role of MTP in the assembly of apoB-containing lipoproteins is still under investigation (21Olofsson S.O. Asp L. Boren J. The assembly and secretion of apolipoprotein B-containing lipoproteins.Curr. Opin. Lipidol. 1999; 10: 341-346Google Scholar, 22Davis R.A. Cell and molecular biology of the assembly and secretion of apolipoprotein B-containing lipoproteins by the liver.Biochim. Biophys. Acta. 1999; 1440: 1-31Google Scholar, 23Raabe M. Veniant M.M. Sulivan M.A. Zlot C.H. Bjorkegren J. Nielsen L.B. Wong J.S. Hamilton R.L. Young S.G. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.J. Clin. Invest. 1999; 103: 1287-1298Google Scholar), MTP is proposed to transport lipids from the ER membrane to the growing apoB polypeptide chain in the ER lumen, thereby allowing proper translocation and folding of apoB to occur (19Wetterau J.R. Lin M.C.M. Jamil H. Microsomal triglyceride transfer protein.Biochim. Biophys. Acta. 1977; 1345: 136-150Google Scholar, 20Gordon D.A. Wetterau J.R. Gregg R.E. Microsomal triglyceride transfer protein: a protein complex required for the assembly of lipoprotein particles.Trends Cell Biol. 1995; 5: 317-321Google Scholar, 21Olofsson S.O. Asp L. Boren J. The assembly and secretion of apolipoprotein B-containing lipoproteins.Curr. Opin. Lipidol. 1999; 10: 341-346Google Scholar, 22Davis R.A. Cell and molecular biology of the assembly and secretion of apolipoprotein B-containing lipoproteins by the liver.Biochim. Biophys. Acta. 1999; 1440: 1-31Google Scholar, 23Raabe M. Veniant M.M. Sulivan M.A. Zlot C.H. Bjorkegren J. Nielsen L.B. Wong J.S. Hamilton R.L. Young S.G. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.J. Clin. Invest. 1999; 103: 1287-1298Google Scholar, 24Wetterau J.R. Gregg R.E. Harrity T.W. Arbeeny C. Cap M. Connolly F. Chu C.H. George R.J. Gordon D.A. Jamil H. Jolibois K.G. Kunselman L.K. Lan S.J. Maccagnan T.J. Ricci B. Yan M. Young D. Chen Y. Fryszman O.M. Logan J.V.H. Musial C.L. Poss M.A. Robl J.A. Simpkins L.M. Slusarchyk W.A. Sulsky R. Taunk P. Magnin D.R. Tino J.A. Lawrence R.M. Dickson J.K. Biller S.A. An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits.Science. 1999; 282: 751-754Google Scholar). MTP has also been proposed to mediate bulk triglyceride transfer into the ER lumen for incorporation into poorly lipidated apoB-containing lipoprotein particles during the process of VLDL and chylomicron assembly (25Kulinski A. Rustaeus S. Vance J.E. Microsomal triglyceride transfer protein is required for luminal accreation of triacylglycerol not associated with apoB, as well as for apoB lipidation.J. Biol. Chem. 2002; 277: 31516-31525Google Scholar, 26Hussain M.M. Iqbal J. Anwar K. Rava P. Dai K. Microsomal triglyceride transfer protein.Front. Biosci. 2003; 8: 500-506Google Scholar). Recent studies have also suggested a role for MTP in the movement of cholesterol ester into the ER lumen for inclusion into nascent apoB-containing lipoprotein particles (27Borradaile N.M. deDreu L.E. Barrett H.R. Behrsin C.D. Huff M.W. Hepatocyte apoB-containing lipoprotein secretion is decreased by the grapefruit flavonoid, naringenin, via inhibition of MTP-mediated microsomal triglyceride accumulation.Biochemistry. 2003; 42: 1283-1291Google Scholar). The initial suggestion that MTP inhibition could be a viable lipid-lowering therapy came with the discovery that functional MTP is absent in individuals with abetalipoproteinemia, a genetic disorder characterized by low plasma cholesterol and triglycerides due to a defect in the assembly and secretion of apoB-containing lipoproteins (28Wetterau J.R. Aggerbeck L.P. Bouma M.E. Eisenberg C. Munck A. Hermier M. Schmitz J. Gay G. Dader D.J. Greg R.E. Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.Science. 1992; 258: 999-1001Google Scholar, 29Berriot-Varoqueaux N. Aggerbeck L.P. Samson-Bouma M.E. Wetterau J.R. The role of the microsomal triglyceride transfer protein in abetalipoproteinemia.Annu. Rev. Nutr. 2000; 20: 633-697Google Scholar). A similar phenotype is observed in MTP knockout mice (23Raabe M. Veniant M.M. Sulivan M.A. Zlot C.H. Bjorkegren J. Nielsen L.B. Wong J.S. Hamilton R.L. Young S.G. Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.J. Clin. Invest. 1999; 103: 1287-1298Google Scholar, 30Chang B.H. Liao W. Li L. Nakamuta M. Mack D. Chan L. Liver-specific inactivation of the abetalipoproteinemia gene completely abrogates VLDL/LDL production in a viable conditional knockout mouse.J. Biol. Chem. 1999; 274: 6051-6055Google Scholar). Abetalipoproteinemia, however, represents an extreme example of MTP inhibition and is not without its clinical sequelae, all of which presumably are related directly or indirectly to fat malabsorption (steatorrhea), vitamin malabsorption, and hepatic and intestinal steatosis (29Berriot-Varoqueaux N. Aggerbeck L.P. Samson-Bouma M.E. Wetterau J.R. The role of the microsomal triglyceride transfer protein in abetalipoproteinemia.Annu. Rev. Nutr. 2000; 20: 633-697Google Scholar, 31Rader D.J. Brewer Jr., H.B. Abetalipoproteinemia. New insights into lipoprotein assembly and vitamin E metabolism from a rare genetic disease.J. Am. Med. Assoc. 1993; 270: 865-869Google Scholar). A less severe, and probably more relevant, example of the consequences of therapeutic MTP inhibition is a related genetic disease, hypobetalipoproteinemia, caused by mutations in apoB (32Herbert P.N. Assmann G. Gotto Jr., A.M. Fredrickson D.S. Familial lipoprotein deficiency: abetalipoproteinemia, hypobetalipoproteinemia, and Tangier disease. Chapter 29.in: Stanbury J.B. Wyngaarden J.B. Fredrickson D.S. Goldstein J.L. Brown M.S. The Metabolic Basis of Inherited Diseases. 5th edition. McGraw Hill, New York1995: 589-621Google Scholar). Heterozygous individuals with this disease possess half of the normal levels of apoB-containing lipoproteins, lack the clinical signs and symptoms of abetalipoproteinemia, and have a normal lifespan (24Wetterau J.R. Gregg R.E. Harrity T.W. Arbeeny C. Cap M. Connolly F. Chu C.H. George R.J. Gordon D.A. Jamil H. Jolibois K.G. Kunselman L.K. Lan S.J. Maccagnan T.J. Ricci B. Yan M. Young D. Chen Y. Fryszman O.M. Logan J.V.H. Musial C.L. Poss M.A. Robl J.A. Simpkins L.M. Slusarchyk W.A. Sulsky R. Taunk P. Magnin D.R. Tino J.A. Lawrence R.M. Dickson J.K. Biller S.A. An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits.Science. 1999; 282: 751-754Google Scholar). We devised a two-stage empirical screening protocol for compound evaluation (33Chang G. Ruggeri R.B. Harwood Jr., H.J. Microsomal triglyceride transfer protein (MTP) inhibitors: discovery of clinically active inhibitors using high-throughput screening and parallel synthesis paradigms.Curr. Opin. Drug Disc. Devel. 2002; 5: 562-570Google Scholar) to identify potent MTP inhibitors with the potential to inhibit hepatic and intestinal apoB-containing lipoprotein assembly and consequently lower plasma total, LDL, and VLDL cholesterol and triglycerides in experimental animals and in humans. In the first stage of the protocol, compounds were evaluated for their ability to inhibit apoB, but not apoA-I secretion, from Hep-G2 cells in a high-throughput, 96-well multiplexed format, essentially as described by Haghpassand, Wilder, and Moberly (34Haghpassand M. Wilder D.E. Moberly J.B. Inhibition of apolipoprotein B and triglyceride secretion in human hepatoma cells (Hep-G2).J. Lipid Res. 1996; 37: 1468-1480Google Scholar). In the second stage of the protocol, confirmed apoB secretion inhibitors were evaluated for their ability to inhibit the MTP-mediated transfer of radiolabeled triolein from synthetic phospholipid donor liposomes to acceptor liposomes (34Haghpassand M. Wilder D.E. Moberly J.B. Inhibition of apolipoprotein B and triglyceride secretion in human hepatoma cells (Hep-G2).J. Lipid Res. 1996; 37: 1468-1480Google Scholar). Using this two-stage screening protocol, we identified CP-94792, a potent inhibitor of apoB, but not apoA-I, secretion (33Chang G. Ruggeri R.B. Harwood Jr., H.J. Microsomal triglyceride transfer protein (MTP) inhibitors: discovery of clinically active inhibitors using high-throughput screening and parallel synthesis paradigms.Curr. Opin. Drug Disc. Devel. 2002; 5: 562-570Google Scholar). Inhibition of apoB secretion was subsequently determined to be through inhibition of MTP activity (33Chang G. Ruggeri R.B. Harwood Jr., H.J. Microsomal triglyceride transfer protein (MTP) inhibitors: discovery of clinically active inhibitors using high-throughput screening and parallel synthesis paradigms.Curr. Opin. Drug Disc. Devel. 2002; 5: 562-570Google Scholar, 35Chang, G., D. S. Cummings, P. H. Dorff, M. L. Gillaspy, J. Hauske, P. A. McCarthy, R. T. Wester, M. T. Zawistoski, C. E. Chandler, A. M. Freeman, M. Haghpassand, H. J. Harwood, Jr., C. A. Marzetta, J. Moberly, J. L. Pettini, Y. E. Savoy, D. E. Wilder, S. Anderson, S. Boyer, J. A. Houser, and J. Vincent. 2001. Discovery of a potent, orally active and clinically efficacious MTP inhibitor via a high-speed synthesis paradigm. Abstract Book of the XIV International Symposium on Drugs Affecting Lipid Metabolism in New York, September 9–12, 2001: 113.Google Scholar). However, although CP-94792 inhibited Hep-G2 cell apoB secretion with an half-maximal inhibition (IC50) of 200 nM and inhibited MTP-mediated triglyceride transfer (rat MTP) with an IC50 of 250 nM, the compound displayed only weak triglyceride lowering activity when administered orally to rats (33Chang G. Ruggeri R.B. Harwood Jr., H.J. Microsomal triglyceride transfer protein (MTP) inhibitors: discovery of clinically active inhibitors using high-throughput screening and parallel synthesis paradigms.Curr. Opin. Drug Disc. Devel. 2002; 5: 562-570Google Scholar). The potent and orally efficacious MTP inhibitor, CP-346086 (4′-trifluoromethyl-biphenyl-2-carboxylic acid [2-(2H-[1,2,4]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl] amide); Fig. 1, inset), was ultimately identified (33Chang G. Ruggeri R.B. Harwood Jr., H.J. Microsomal triglyceride transfer protein (MTP) inhibitors: discovery of clinically active inhibitors using high-throughput screening and parallel synthesis paradigms.Curr. Opin. Drug Disc. Devel. 2002; 5: 562-570Google Scholar, 35Chang, G., D. S. Cummings, P. H. Dorff, M. L. Gillaspy, J. Hauske, P. A. McCarthy, R. T. Wester, M. T. Zawistoski, C. E. Chandler, A. M. Freeman, M. Haghpassand, H. J. Harwood, Jr., C. A. Marzetta, J. Moberly, J. L. Pettini, Y. E. Savoy, D. E. Wilder, S. Anderson, S. Boyer, J. A. Houser, and J. Vincent. 2001. Discovery of a potent, orally active and clinically efficacious MTP inhibitor via a high-speed synthesis paradigm. Abstract Book of the XIV International Symposium on Drugs Affecting Lipid Metabolism in New York, September 9–12, 2001: 113.Google Scholar, 36Wilder, D. E., Y. E. Savoy, J. L. Pettini, S. F. Petras, G. Chang, J. Vincent, C. E. Chandler, and H. J. Harwood, Jr. 2001. CP-346086: a microsomal triglyceride transfer protein inhibitor that decreases total, VLDL, and LDL cholesterol and triglycerides by up to 70% in experimental animals and in humans. Abstract Book of the XIV International Symposium on Drugs Affecting Lipid Metabolism in New York, September 9–12, 2001: 46.Google Scholar, 37Wilder D.E. Savoy Y.E. Pettini J.L. Petras S.F. Chang G. Vincent J. Chandler C.E. Harwood Jr., H.J. The microsomal triglyceride transfer protein inhibitor CP-346086 decreases total, VLDL, and LDL cholesterol and triglycerides in experimental animals and in humans (Abstract).Circulation. 2001; 104: 176Google Scholar) by 1) employing a robotics-assisted parallel synthesis strategy as a means of developing structure-activity relationships and improving in vitro potency, and 2) using in vitro hepatic microsomal clearance and in vivo triglyceride lowering as guides for improving pharmacokinetic properties. In this report, we describe the biochemical mechanism of action of CP-346086 that leads to its LDL cholesterol-, VLDL cholesterol-, and triglyceride-lowering efficacy in experimental animals and in humans. Sodium [2-14C]acetate (56 mCi/mmol), [14C]triolein (110 mCi/mmol), cholesteryl [1-14C]oleate (55 mCi/mmol), [3H]triolein (25 Ci/mmol), [3H]egg phosphatidylcholine (50 mCi/mmol), and Aquasol-2 were from New England Nuclear (Boston, MA). [3H]glycerol (20 Ci/mmol) was from American Radiochemicals (St. Louis, MO). Ready Safe™ liquid scintillation cocktail was from Beckman Instruments (Fullerton, CA). Dulbecco's modified Eagle's medium (DMEM), l-glutamine, and gentamicin were from GIBCO Laboratories (Grand Island, NY). Heat-inactivated fetal bovine serum was from HyClone Laboratories (Logan, UT). DEAE cellulose was from Whatman International (Maidstone, England). Silica gel 60C TLC plates were from Eastman Kodak (Rochester, NY). BCA protein assay reagent was from Pierce (Rockford, IL). Cholesterol/HP reagent (Cat. 1127578), TG/GPO reagent (Cat. 1128027), Preciset Cholesterol Calibrator Set (Cat. 125512), and Precitrol-N serum (Cat. 620212) were from Boehringer Mannheim (Indianapolis, IN). Cholesterol CII reagent kit (Cat. 276-64909), Triglyceride E reagent kit (Cat. 432-40201), Standard Cholesterol CII Solution (Cat. 277-64939), and Standard Triglyceride G Solution (Cat. 998-69831) were from Waco Chemicals USA (Richmond, VA). Hep-G2 cells were from the American Type Culture Collection (Rockville, MD). Mouse anti-human apoB monoclonal antibodies (MoAB-012), goat anti-human apoB polyclonal antibodies (AB-742), mouse anti-human apoA-I monoclonal antibodies (MAB-011), goat anti-human apoA-I polyclonal antibodies (AB-740), and human apoA-I purified standard (ALP10) were from Chemicon (Temecula, CA). B6CBAF1J mice were from Jackson Laboratory (Bar Harbor, ME). Transgenic huA1/CIII/cholesteryl ester transfer protein (CETP) mice, originally obtained from Charles River (Boston, MA), were bred on site. Sprague Dawley rats were from Charles River. RMH 3200 laboratory meal was from Agway, Inc. (Syracuse, NY). AIN76A semipurified diet was from US Biochemicals (Cleveland, OH). F0739 liquid diet powder was from Bio-Serve, Inc. (Frenchtown, NJ). Fast protein liquid chromatography (FPLC) instrumentation was from Gilson, Inc. (Middletown, WI). Superose-6 gel filtration columns were from Pharmacia (Piscataway, NJ). Postcolumn reaction (PCX) instrumentation was from Pickering Laboratories (Mountain View, CA). All other chemicals and reagents were from previously listed sources (38Harwood Jr., H.J. Barbacci-Tobin E.G. Petras S.F. Lindsey S. Pellarin L.D. 3-(4-chlorophenyl)-2-(4-diethylaminoethoxyphenyl)-A-pentenonitrile monohydrogen citrate and related analogs: reversible, competitive, first half-reaction squalene synthetase inhibitors.Biochem. Pharmacol. 1997; 53: 839-864Google Scholar, 39Petras S.F. Lindsey S. Harwood Jr., H.J. HMG-CoA reductase regulation: use of structurally diverse first half-reaction squalene synthetase inhibitors to characterize the site of mevalonate-derived nonsterol regulator production in cultured IM-9" @default.
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