ACAT inhibitor

Burnett and coworkers have described the synthesis of a very potent class of cholesterol absorption inhibitors (CAI) typified by the original lead compound in this series the compound I showed in Fig. 42 (SCH 48461). This 2-azetidinone has resulted as an effective inhibitor of cholesterol absorption in a cholesterol-fed hamster model [9]. Subsequently, the same molecule has been shown to reduce serum cholesterol in human clinical trials [382]. Although this class of compounds has been initially designed as acyl coenzyme A cholesterol transferases (ACAT) inhibitors, early structure-activity studies demonstrated a striking divergence of in vitro ACAT inhibition and in vivo activity in the cholesterol-fed hamster. A detailed examination of this molecule indicated that the hypocholesterolemic... 

Intestinal acyl-CoA cholesterol acyltransferase (ACAT-2, also present in liver), which esterifies free cholesterol with palmitic or oleic acid, is another enzyme that was identified early on as a potential target to inhibit cholesterol absorption because most cholesterol in chylomicrons is esterified before being secreted by enterocytes (6, 14). As for CEL, various inhibitors of this enzyme were also developed and tested with mixed results (10, 15-17). However, the importance of ACAT-2 was later confirmed by studies of gene-knockout mice, which exhibit markedly reduced cholesterol absorption and atherosclerosis when fed Western diet (18). Nonetheless, progress in developing effective ACAT inhibitors has been slow, in part because of concerns about the potential for deleterious systemic effects resulting from inhibition of the more widely expressed ACAT-1 (19). Despite these... 

Leon, C., Hill, J. S., and Wasan, K. M. (2005) Potential role of acyl-coenzyme Axholesterol transferase (ACAT) inhibitors as hypolipidemic and antiatherosclerosis drugs. Pharm. Res. 22, 1578-1588. 

Third, acyl-CoA cholesterol acyltransferase (ACAT) [EC 2.3.1.26], an enzyme that works after the formation of cholesterol, was considered a unique target of inhibition [32], ACAT catalyzes the synthesis of cholesteiyl esters from cholesterol and long-chain fatty acyl-CoA. ACAT plays important roles in the body, for example, in the absorption of dietary cholesterol from the intestines, production of lipoprotein in liver and formation of foam cells from macrophages in arterial walls. Therefore, ACAT inhibition is expected not only to lower plasma cholesterol levels but also to have a direct effect at the arterial wall. A number of synthetic ACAT inhibitors such as ureas, imidazoles, and acyl amides have been developed [33], Several groups have searched for novel ACAT inhibitors... 

DR Sliskovic, AD White. Therapeutic potential of ACAT inhibitors as lipid lowering and anti-atherosclerotic agents. Trends Pharmacol Sci 12 194-199, 1991. 

H Tomoda, N Tabata, DJ Yang, H Takayanagi, S Omura. Terpendoles, novel ACAT inhibitors produced by Albophoma yamanashiensis. III. Production, isolation and structure elucidation of new components. J Antibiot 48 793-804, 1995. 

ASJ Katocs, CH Wang, EE Largis. The hypercholesterolemic activity of the ACAT inhibitor CL 283,546 in raf rabbit and monkey. FASEB J 2 A1219, 1988. 

MatsudaK(1994) ACAT inhibitors as antiatherosclerotic agents compounds and mechanisms. 

A typical method using liquid/liquid extraction was described by Shum et al. (1994) for the determination of an ACAT inhibitor in rat plasma. Internal standard,... 

Additionally, a number of biologically significant molecules have in their structure a chiral nonracemic sulfinyl group. Among these molecules (Fig. 1), it is worth noting the new immunosuppressive thiaspirane sulfoxide Nuphar alkaloid type la and lb,13 the gastric antisecretory omeprazole 2,14 the new potassium channel activators of Rhone Poulenc aprikalim 3,15 the cyclic hexapeptide waiakeamide 4,16 the ACAT inhibitor 5,17 and the potent human immunodeficiency virus type 1 protease inhibitor 6.18... 

NMDA glycine-site antagonists <03BMCL3553>, 5-aryl-pyrazolo[3,4-6]pyridazines as inhibitors of glycogen synthase kinase-3 <03BMCL1581>, and 3-arylamino- and 3-cycloalkylamino-5,6-diphenylpyridazines as ACAT inhibitors <03AP563>. 

Dozeman, G. J. Fiore, P. J. Puls, T. P. Walker, J. C., Chemical Development of a Pilot Scale Process for the ACAT Inhibitor 2,6-Diisopropylphenyl [(2,4,6-Triisopropylphenyl)acetyl]sulfa-... 

Bellemin, R., Decerprit, J., and Festal, D., New indole derivatives as ACAT inhibitors. Synthesis and structure-activity relationships, Eur. J. Med. Chem. Chim. Ther, 31, 123, 1996. 

Patankar, S.J. and Jurs, P.C. (2000) Prediction of IC50 values for ACAT inhibitors from molecular structure. J. Chem. Inf. Comput. Sci., 40, 706—723. 

Huang X-H, Tomoda H, Nishida H, Masuma R, Omura S. Terpendoles, novel ACAT inhibitors produced by Apbophoma yamanashiensis I. Production, isolation and biological properties. J Antibiot 43 1-4, 1995. 

The cloning of ACAT-2 (R.A. Anderson, 1998 S. Cases, 1998 R Oelkers, 1998) revealed a protein of simitar size to ACAT-1, with a novel N-terminus but a C-terminus highly similar to ACAT-1. In adult humans, ACAT-2 is expressed in the apical region of intestinal enterocytes and in hepatocytes. Disruption of the ACAT-2 gene in mice led to dramatic reduction in cholesterol absorption and prevention of hypercholesterolemia (A.K.K. Buhman, 2000). The data suggest that, in humans, ACAT-1 plays a critical role in foam-cell formation and cholesterol homeostasis in extrahepatic tissues, whereas ACAT-2 has an important role in absorption of dietary cholesterol [29]. Interest in ACAT inhibitors as a therapeutic strategy has been revived by liver-specific knockdown of ACAT-2 in atherosclerotic-prone mice, which significantly reduced aortic atherosclerotic lesions (T.A. Bell, 2006). 

Cholesteryl esters are quantitatively minor constituents (5-15% of total lipids) of VLDLs but the amount of cholesteryl esters relative to TG in VLDLs increases when rats are fed a high cholesterol diet. The esterification of cholesterol is mediated by two distinct acyl-CoA cholesterol acyltransferases (ACATs) [11]. Inhibition of cholesterol esterification with an ACAT inhibitor in hepatocytes decreased apo B secretion in some studies but not in others. For example, severe reduction in cholesteryl ester content of hepatoma cells decreased apo B secretion, whereas increased cholesteryl ester content did not stimulate apo B secretion. In mouse liver and intestine, the majority of cholesteryl esters are made by ACAT2. Nevertheless, normal quantities of apo B-containing lipoproteins are produced in mice lacking ACAT2 despite the absence of essentially all hepatic ACAT activity. However, ACAT2-deficient mice exhibit reduced intestinal absorption of cholesterol and are resistant to diet-induced hypercholesterolemia (R.V. Farese, 2(X)0). Thus, the observed reduction of plasma cholesterol in response to ACAT inhibitors is probably due to decreased cholesterol absorption rather than decreased VLDL secretion. 

Example compounds affecting the adrenal cortex include acrylonitrile, amino-gluthemide, amytriptyline, aniline, carbon tetrachloride (Colby et al. 1994), chloroform, cimetidine, etomidate, domperidone, fluphenazine, glycyrrhizin, ketoconazole (Loose et al. 1983), methanol, parathion, pentabarbitone, phencyclidine, pyra-zole, spironolactone, tamoxifen, and urethane (Colby and Longhurst 1992 Szabo and Sandoz 1997). Amytriptyline and cimetidine reduce corticosterone secretion, whereas pentobarbitone and phencyclidine increase its secretion. Etomidate inhibits 11(3- and 17a-hydroxylating reactions. Spironolactone affects cytochrome P450 enzymes (Kossor et al. 1991), and domperidone blocks cortisol secretion. Some ACAT inhibitors cause adrenal cytotoxicity (Wolfgang et al. 1995). 

Trivedi, B.K., Holmes, A., Stoeber, T.L., Blankley, C.J., Roark, H.W., et al. Inhibitors of acyl-CoA cholesterol acyltransferase. 4. A novel series of urea ACAT inhibitors as potential hypocholesterolemic agents. J. Med Chem. 36 3300-3307. 

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