RP 64477: A potent inhibitor of Acyl-coenzyme A: Cholesterol O-acyltransferase with low systemic bioavailability

Biochemical Pharmacology

Volumn 51, Issue 4, 1996, Pages 413-421

  Bello, Akintunde A ^a   Bright, Colin ^a   Burton, Brenda J ^a   Bush, Raymond C ^a   Casey, James H ^a   Dron, Donald I ^a   Facchini, Vincenzo ^a   Joannou, Parascevas P ^a   Parrott, David P ^a   Riddell, David ^a   Roberts, Simon A ^a   Williams, Robert J ^a  

^a SANOFI   (France)

Author keywords

Absorption; ACAT; Bioavailability; Cholesterol; Hypocholesterolaemic; RP 64477

Indexed keywords

CHOLESTEROL; CHOLESTEROL ACYLTRANSFERASE; CHOLESTEROL ACYLTRANSFERASE INHIBITOR; CHOLIC ACID; HYPOCHOLESTEROLEMIC AGENT; N (5 BUTYLAMINOCARBONYL 2 METHYLTHIOPHENYL) 4 DECYLOXYBENZAMIDE; RADIOISOTOPE;

ADRENAL GLAND; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTERY; ARTICLE; CELL LINE; CHOLESTEROL DIET; CHOLESTEROL METABOLISM; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG EXCRETION; DRUG FECES LEVEL; ENZYME INHIBITION; HAMSTER; HUMAN; HUMAN CELL; INTESTINE; KIDNEY CLEARANCE; LIVER; MALE; MARMOSET; NONHUMAN; ORAL DRUG ADMINISTRATION; PRIORITY JOURNAL; RABBIT; RAT; SWINE;

ACYL COENZYME A; ANIMALS; BENZAMIDES; BIOLOGICAL AVAILABILITY; CALLITHRIX; CELL LINE; CHOLESTEROL; CRICETINAE; ENZYME INHIBITORS; ERYTHROCYTES; HUMANS; INTESTINAL ABSORPTION; KINETICS; MALE; ORGAN SPECIFICITY; RABBITS; RATS; RATS, SPRAGUE-DAWLEY; STEROL O-ACYLTRANSFERASE; SWINE; TISSUE DISTRIBUTION; TUMOR CELLS, CULTURED;

EID: 0030049343     PISSN: 00062952     EISSN: None     Source Type: Journal    
DOI: 10.1016/0006-2952(95)02186-8     Document Type: Article

References (27)

1. Lipid Research Clinics Program, The Lipid Research Clinics Coronary Primary Prevention Trial Results: I. Reduction in incidence of coronary heart disease. J A M A 251: 351-364, 1984.
2. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, Huttenen JK, Kaitaniemi P, Koskinen P, Manninen V, Maenpaa H, Malkonen M, Mantarri M, Norola S, Pasternack A, Pikkarainen J, Romo M, Sjoblom T and Nikkila EA, Helsinki Heart Study: Primary-prevention trial with gemfibrozil in middle aged men with dyslipidaemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 317: 1237-1245, 1987.
3. Watts GF, Lewis B, Brunt JNH, Lewis ES, Coltart DJ, Smith LDR, Mann JI and Swan AV, Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas's Atherosclerosis Regression Study (STARS). Lancet 33: 563-569, 1992.
4. Contermans J and Erkelens DW, Combination drug therapy in the treatment of severe hyperlipidaemia. Atherosclerosis 97: S21-S26, 1992.
5. Kesaniemi YA and Miettinen TA, Cholesterol absorption efficiency regulates plasma cholesterol level in the Finnish population. Eur J Clin Inv 17: 391-395, 1987.
6. Becker M, Staab D and Von Bergmann K, Treatment of severe familial hypercholesterolaemia in childhood with sitosterol and sitostanol. J Pediatr 122: 292-296, 1993.
7. Tso P and Balint JA, Formation and transport of chylomicrons by enterocytes to the lymphatics. Am J Physiol 250: G715-G726, 1986.
8. Norum KR, Lilljequist AC, Helgerud P, Normann ER, Mo A and Selbekic B, Esterification of cholesterol in human small intestine. The importance of acyl-CoA: cholesterol acyl transferase. Eur J Clin Inv 9: 55-62, 1979.
9. Windler E, Rucker W, Greeve J, Reimitz H and Greten H, Influence of the acyl-Coenzyme A: cholesterol acyltransferase inhibitor octimibate on cholesterol transport in rat mesenteric lymph. Arzneim Forsch Drug Res 40: 1108-1111, 1990.
10. Krause BR, Anderson M, Bisgaier CL, Bocan T, Bousley R, De-Hart P, Essenburg A, Hamelehle K, Homan R, Kieft K, McNally W, Stanfield R and Newton RS, In vivo evidence that the lipidregulating activity of the ACAT inhibitor CI-976 in rats is due to inhibition of both intestinal and liver ACAT. J Lipid Res 34: 279-294, 1993.
11. Bennett Clark S and Tercyak AM, Reduced cholesterol transmucosal transport in rats with inhibited mucosal acyl CoA: cholesterol acyltransferase and normal pancreatic function. J Lipid Res 25: 148-159, 1984.
12. Hieder JG, Pickens CE and Kelly LA, Role of acyl CoA: cholesterol acyltransferase in cholesterol absorption and its inhibition by 57-118 in the rabbit. J Lipid Res 24: 1127-1134, 1983.
13. Harnett KM, Walsh CT and Zhang L, Effects of Bay o 2752, a hypercholesterolaemic agent, on intestinal taurocholate absorption and cholesterol esterification. J Pharm Exp Ther 251: 502-509, 1989.
14. Lichenstein AH and Brecher P, Properties of acyl CoA: cholesterol acyltransferase in rat liver microsomes. J Biol Chem 255: 9098-9104, 1980.
15. Weiser MM, Intestinal epithelial cell surface membrane glycoprotein synthesis. J Biol Chem 248: 2536-2541, 1973.
16. Folch J, Lees M and Sloane Stanley GH, A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226: 497-509, 1957.
17. Field FJ, Albright E and Mathur SN, Regulation of cholesterol esterification by micellar cholesterol in CaCo2 cells. J Lipid Res 28: 1057-1066, 1987.
18. Havekes LM, DeWit ECM and Princen HMG, Cellular free cholesterol in HepG2 cells is only partially available for down regulation of low density lipoprotein receptor activity. Biochem J 247: 739-746, 1987.
19. Via DP, Pons L, Dennison DK, Fanslow AE and Bernini F, Induction of acetyl-LDL receptor activity by phorbol ester in a human monocyte cell line THP-1. J Lipid Res 30: 1515-1524, 1989.
20. Vahouny GV and Treadwell CR, Pancreatic sterol ester hydrolase. Methods Enzymol 15: 537-543, 1969.
21. Stokke KT and Norum NR, Determination of lecithin:cholesterol acyltransferase in human blood plasma. Scand J Clin Lab Inv 27: 21-27, 1971.
22. Zilversmit DB, A single blood sample dual isotope method for the measurement of cholesterol absorption in rats. Proc Soc Exp Biol Med 140: 862-865, 1972.
23. Billheimer JT and Gilles PJ, Intracellular cholesterol esterification, In Advances in cholesterol research (Ed. Esfaham M and Swaney JB) 1-45, Telford Press, 1990.
24. Riddell D, Bright C, Burton BJ, Bush RC, Harris NV, Hele D, Moore UM, Naik K, Parrott DP, Smith C and Williams RJ, Hypolipidaemic properties of RP 73163, a potent and systemically bioavailable inhibitor of ACAT activity in animals fed diets low in cholesterol, (submitted for publication).
25. Harris WS, Dujovne CA, von Bergmann K, Neal J, Akester J, Windsor SL, Greene D and Look Z, Effects of the ACAT inhibitor CL 277,082 on cholesterol metabolism in humans. Clin Pharmacol Ther 48: 189-194, 1990.
26. Bigonzi, F, XVIth Congress of the European Society of Cardiology, Berlin, 10th-14th September 1994.
27. Hainer JW, Greg Terry J, Connell JM, Zyruk H, Jenkins RM, Shand DL, Gilles PJ, Livak KL, Hunt TL and Crouse JR, Effect of the ACAT inhibitor DUP 128 on cholesterol absorption and serum cholesterol in man. Clin Pharmacol Ther 56: 65-74, 1994.