Cholesterol transferase inhibitor

A number of enantioselective Simmons-Smith-type cyclopropanations have been disclosed, of which three classic examples are discussed in this section [19]. In the first, Charette described the use of a dioxaborolane (111, Scheme 15.13) as an effective chiral controller group [68]. The presence of the basic amide C=0 was found to be critical for directing the cyclopropanation reagent to a single olefin diastereoface. Treatment of allylic alcohols such as 110 with 111 and Zn(CH2l)2 led to the formation of intermediate boronates that subsequently underwent cyclopropanation with excellent yields and enantioselectivities. An impressive iterative application of this method was showcased by Charette in a total synthesis of the natural product U-1065305 (113), a cholesterol transferase inhibitor [69]. 

This reaction has been used in the large-scale preparation of an intermediate in the synthesis of a cholesterol acyl-transferase inhibitor.27... 

Inskeep, P. B., K. M. Davis, and A. E. Ree. Pharmacokinetics of the acyl coenzyme A cholesterol acyl transferase inhibitor CP-105,191 in dogs-the effect of food and sesame oil on systemic exposure following oral dosing. J Pharm Sci 1995 84(2) 131-133. Satchithanandam, S., M. Reicks, R. J. Calvert, M. M. Cassidy, and D. Kritchevsky. Coconut oil and sesame... 

Very recently, (3-lactam antibiotics have been shown to offer neuroprotection by increasing glutamate transporters expression via gene activation [15] in addition, the discoveries of new biologically active (3-lactams such as cholesterol acyl transferase inhibitors [16-18], thrombin inhibitors [19], human cytomegalovirus protease inhibitors [20], matrix-metallo protease inhibitors [21], inhibitors of human leukocyte elastase (HLE) [22, 23] and cysteine protease [24, 25], and apoptosis inductors [26, 27] have provided much needed motivation for continuous development of new (3-lactam systems. 

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... 

Further examples of the photolytic generation of thioaldehydes from phenacyl sulfides include the synthesis of 3,6-dihydro-27/-thiopyrans bearing a variety of functions at C-2 of which some are potent acyl-CoA-cholesterol acyl-transferase inhibitors (Equation 135) <1996BMC1493>. 

The fcij-urea derivative YM 17E has been described as an inhibitor of acylcoenzyme A cholesterol transferase (ACAT), a potential anti-cholesterolemic drug." ... 

The primary transporter of cholesterol in the blood is low density Hpoprotein (LDL). Once transported intraceUularly, cholesterol homeostasis is controlled primarily by suppressing cholesterol synthesis through inhibition of P-hydroxy-P-methyl gluterate-coenzyme A (HMG—CoA) reductase, acyl CoA—acyl transferase (ACAT), and down-regulation of LDL receptors. An important dmg in the regulation of cholesterol metaboHsm is lovastatin, also known as mevinolin, MK-803, and Mevacor, which is an HMG—CoA reductase inhibitor (Table 5). 

Veinberg G, Vorona M, Shestakova I, Kanepe I, Lukevics E (2003) Some of the more notable advances concern the development of mechanism-based serine protease inhibitors of elastase, cytomegalovirus protease, thrombin, prostate specific antigen, and cell metastasis and as inhibitors of acyl-CoA cholesterol acyl transferase. Curr Med Chem 10 1741... 

The combination of a lipophilic terpenoid fragment with a polar polyketide moiety has produced structures with significant biological activity. Thus the pyropenes A-R, e.g. 5.171, from a strain of Aspergillus fumigatus are powerful inhibitors of acyl CoA-cholesterol acyl transferase, an enzyme that contributes to the absorption of dietary cholesterol and the accumulation of cholesterol esters. These are problems that lead to atherosclerosis. 

The squalestatins, e.g. 6.28, also known as the zaragozic adds, have attracted considerable interest as inhibitors of squalene synthase and hence of cholesterol biosynthesis and lipid deposition in the circulatory system. They are also inhibitors of farnesyl protein transferase and thus they may have other potentially useful biological applications. They are formed by Phoma spedes and also by Setosphaeria khartoumensis. The squalestatins are characterized by a dioxabicyclo-octane core bearing three carboxyl groups and two polyketide chains, one of which is attached as an ester. The biosynthetic incorporation of succinic acid into part of the bicyclo-octane, together with its oxygenation pattern, indicate that it may be derived via oxaloacetic acid. Both the polyketide chains have several pendant methyl groups attached to them, which arise from methionine, whilst benzoic add ads as a starter unit for one of the chains. These complex structures are thus the summation of several biosynthetic pathways. 

Pyripyropenes were potent inhibitors of A. fumigatus acyl CoAxholesterol acyl transferase, with IC50 values ranging from 53 nM (113c) to 268 nM (113d) [316], Cholesterol absorption in hamsters was inhibited by 113a [316]. Pyripyropenes displayed no cytotoxicity to Vero cells at 177 pM, no antimicrobial activity at 1.77 mM, and no acute toxicity to ddY mice at 200 mg/kg [319],... 

Data for Z. A IC50 (rat SQS) 15 nMol lowering of the cholesterol level in marmosets by 50% after 7 daily doses of 10 mg/kg. SQS catalyzes the reductive dimerization of famesyl pyrophosphate to squalene. All Z. thus show pronounced antifungal activities (IC50 in nMol range). As inhibitors of famesyl protein transferase the Z. are potential cytostatic agents. Several total syntheses of the Z. have been reported. Z. are structurally related to the CP compounds CP-225,9I7 and CP-263,1141... 

Structure—activity relationship study and total synthesis of pyripyropene A as a potent and selective inhibitor of acyl-CoA cholesterol acyl transferase (ACAT2) 13YGK830. 

Dietary cholesterol is absorbed by intestinal ABC cholesterol transporter (Chapter 41). Once inside the cell, cholesterol is esterified by acyl CoA-cholesterol-acyl transferase (ACAT) to form the hydro-phobic cholesteryl ester. This reaction facilitates and maximises absorption of cholesterol, which is probably an advantage to people deprived of cholesterol-rich food such as meat. Unfortunately, efficient absorption of cholesterol is not an advantage to the affluent. However, margarines enriched with plant sterols have been used to inhibit cholesterol absorption in an attempt to lower blood cholesterol. Research is under way to develop ACAT inhibitors that potentially are cholesterol-lowering drugs. Ezetimibe is a new drug that inhibits cholesterol absorption by inhibition of the intestinal cholesterol-transporter protein NPCILI (Niemann-Pick Cl-like protein 1). 

Acyl-CoA cholesterol acyl transferase (ACAT) catalyzes the intracellular formation of cholesteryl esters (CE) in all mammalian cells. It has been implicated as a key enzyme involved in cholesterol absorption, very low density lipoprotein secretion, and the formation of lipid-laden macrophages. The accumulation of CE in macrophage-derived foam cells is characteristic of the early step in the development of atherosclerosis. ACAT inhibitors reduced TC levels without affecting HDL-C. This can be attributed to decreased intestinal cholesterol absorption based on binding to bile acid (Turley SD. and Herndon MW. 1994)... 

In his synthesis of the CP molecules, Nicolaou employed an Amdt-Eistert homologation of an advanced intermediate. These fungal-derived natural products are inhibitors of famesyl transferase, which could be used to control the level of semm cholesterol. Due to its sensitive nature, intermediate 27 was converted into diazo ketone 29 via the acyl mesylate 28 as opposed to an acid chloride. The diazo ketone 29 was immediately dissolved in DMF H2O and heated to 120 °C in the presence of silver oxide. This gave the homologated product 30 in 35% yield, which was subsequently transformed into CP molecule 31. 

Figure 12. Acyl-CoA cholesterol O-transferase (ACAT) inhibitors (29).

---