Acyl CoA:cholesterol acyltransferase inhibitors

JF Reindel, MA Dominick, TM Bocan, AW Gough, EJ McGuire. Toxicologic effects of a novel acyl-CoA cholesterol acyltransferase inhibitor in cynomolgus monkeys. Toxicol Pathol 22 510-518, 1994. 

BM Kwon, MK Kim, SHLee, JAKim, IR Lee,YKKim, SHBok. Acyl-CoA Cholesterol acyltransferase inhibitors from Magnoha obovata. Planta Medica 63 550-551, 1997. 

TF Woolf, SM Bjorge, AE Black, A Holmes, T Chang. Metabolism of the acyl-CoA Cholesterol acyltransferase inhibitor 2,2-dimethyl-7V-(2,4,6-trimethoxy-phenyl)dodecanamidc in rat and monkey. Drug Metab Dispos 19 696, 1991. 

Nucleophilic tert-prenylation. When using prenylboranes instead of tert-prenylboranes, tert-prenylation of 3-chloroindolenines becomes possible. The Danishefsky tert-prenylation has also been extensively used for the synthesis of 3-tert-prenylindoles which can be obtained from 2-tert-prenylated precursors (see Sect. 4). The 1995 synthesis of the acyl-CoA-cholesterol acyltransferase inhibitor gypsetin (94) [91, 92] was the first occasion to publish that elegant reaction (Scheme 19) [88, 93]. On treatment of phthalimide-protected tryptophan methyl ester (85) with tcrt-BuOCl, the 3-chloroindolenine is formed in sim, which is nucleophilicaUy attacked by prenyl-9-BBN with regioinversion of the prenyl group. Hydrazinolysis afforded 2-tert-prenyltryptophan methyl ester (91). 

Another example of Negishi coupling using Pd(OAc)2 on commercial scale was explored by Praveen et al. [37] from Dr. Reddy s Laboratories for the synthesis of an acyl-CoA cholesterol acyltransferase inhibitor, ezetimibe 102. The carboxylic acid 98 was converted into acid chloride 99 and directly incorporated in a large-scale Negishi coupling with arylzinc complex 100 in the presence of Pd(OAc)2 catalyst to afford the aryl ketone 101 (Scheme 9.25). 

SCHEME 9.25 An acyl-CoA cholesterol acyltransferase inhibitor, ezetimibe. 

Arai N, Shiomi K, Tomoda H, Tabata N, Yang DJ, Masuma R, Kawakubo T, Omura S (1995) Isochromophilones III VI, Inhibitors of Acyl-CoA Cholesterol Acyltransferase Produced by Penicillium multicolor FO-3216. J Antibiot 48 696... 

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... 

Tomoda, H. Kim, Y. K. Nishida, H. Musuma, R. Omura, S. 1994. Pyripy-ropenes, novel inhibitors of acyl-CoA Cholesterol acyltransferase produced by Aspergillus fumigatus. I. Production, isolation, and biological properties. /. Antibiotics, 47,148-153. 

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... 

Figure 7 Process of lipid droplet formation in macrophages and inhibition sites of inhibitors. ACAT (acyl-CoA cholesterol acyltransferase) and ACS (acyl-CoA synthetase).

H Tomoda, H Nishida, YK Kim, R Obata, T Sunazuka, S Omura, J Bordner, M Guadllana, PG Dormer, AB Smith III. Relative and absolute stereochemistry of pyripyropene A, a potent, bioavailable inhibitor of acyl-CoA cholesterol acyltransferase. J Am Chem Soc 116 12097-12098, 1994. 

H Tomoda, H Nishida, R Masuma, J Cao, S Okuda, S Omura. Purpactins, new inhibitors of acyl-CoA cholesterol acyltransferase produced by Penicilliumpurpur-ogenum. I. Production, isolation and physico-chemical and biological properties. J Antibiot 44 136-143, 1991. 

S Omura, H Tomoda, YK Kim, H Nishida. Pyripyropenes, highly potent inhibitors of acyl-CoA cholesterol acyltransferase produced by Aspergillus fumigatus. J Antibiot 46 1168-1169, 1993. 

Enniatins (Fig. 44) are produced by Fusarium species. Enniatin B exhibits binding to alkali ions, as well as valinomycin. While valinomycin shows preferential binding to K, Rb, and Cs over Na", enniatin B is considerably less specific Enniatins D, E and F were isolated from Fusarium sp. FO-1305 as inhibitors of acyl-CoA cholesterol acyltransferase (ACAT), by Tomoda et al. in 1992. The IC50 values of enniatins D, E and F against ACAT in an enzyme assay using rat liver microsomes are 87, 57 and 40 pM, respectively ... 

Presumably the cyclopentyl rest fills, in an optimal manner, a hydrophobic pocket of the active site of the enzyme. The cyclopentyl group has also proven advantageous in replacing a em-dimethyl in a series of inhibitors of acyl-CoA-cholesterol acyltransferase, which is an enzyme implied in the absorption of the alimentary cholesterol." ... 

Although less well studied than diketopiperazines, biologically active compounds containing a diketomorpholine ring system are also known (e. g., Lateritin, an inhibitor of acyl-CoA-cholesterol acyltransferase [125]). 

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. 

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. 

Inhibitors of acyl CoA-cholesterol acyltransferase (ACAT) are currently being Investigated as cholesterol-lowering or antiatherosclerotic agents. In addition to its role in foam cell formation, ACAT also is required for esterification of cholesterol in intestinal mucosal cells and for synthesis of cholesterol esters in hepatic VLDL formation. Thus, ACAT inhibitors have the potential of providing three beneficial effects in patients with hypercholesterolemia decreased cholesterol absorption, decreased hepatic VLDL synthesis, and decreased foam cell formation. Initial successes at inhibiting ACAT were dampened by the discovery of accompanying adrenal toxicity. Subsequent structural modifications have lead to the development of... 

Several target enzymes in the cholesterol biosynthesis pathway have been targeted in attempts to lower blood cholesterol. The HMG-CoA reductase inhibitor (106) is 10 times more potent than lovastatin <93JMC3658>, and both SQ-33600 (107) and XU 62-320 (108) also inhibit this enzyme . The indole compound SaH 57-118 (109) inhibits acyl CoA cholesterol acyltransferase and lowers cholesterol absorption in rabbits by 65% . 

Pyridazine derivatives as novel acyl-CoA cholesterol acyltransferase (ACAT) inhibitors 05JHC395. 

In the s5mthesis of SMP-797 442 as a new potent acyl-CoA cholesterol acyltransferase (ACAT) inhibitor, a modified Friedlander annulation was used (Figure 22) (05T10081). 

Acaterin (1), isolated from a culture broth of Pseudomonas sp. A92 by Endo and co-workers/ is one of the acyl-CoA cholesterol acyltransferase (ACAT) inhibitors that are expected to be effective for the treatment of atherosclerosis and hypercholesterolemia, and also has remarkable antitumor activity. Since the total synthesis of acaterin reported by Kitahara and co-workers, synthetic strategies based on the MBH reaction have more recently been reported for this molecule almost simultaneously by three different research groups. Franck and Figadere first reported the synthesis of racemic acaterin 1 by condensation of ot,(3-unsaturated y-lactone 2 (99% ee) and octanal via a DABCO-mediated MBH reaction (Scheme 5.1). Unfortunately, using chiral (S)-2 (99% ee) as a reactant. 

Prod, by Penicillium asperosporum. Inhibitor of acyl-CoA cholesterol acyltransferase. Yellow powder, [oc] —8.5 (c, 0.2 in MeOH). Related to Penicillide, P-10025. Stereoisomer Antibiotic AS 186G, AS 186G C43H460,2 M 754.829... 

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