Inhibitors of cholesterol

The first study was conducted to determine whether carotenoids and cholesterol share common pathways (transporters) for their intestinal absorption (During et al., 2005). Differentiated Caco-2 cells on membranes were incubated (16 h) with a carotenoid (1 pmol/L) with or without ezetimibe (EZ Zetia, an inhibitor of cholesterol transport), and with or without antibodies against the receptors, cluster determinant 36 (CD36) and scavenger receptor class B, type I (SR-BI). Carotenoid transport in Caco-2 cells (cellular uptake + secretion) was decreased by EZ (lOmg/L) as follows P-C and a-C (50% inhibition) P-cryptoxanthin and LYC (20%) LUT ZEA (1 1) (7%). EZ reduced cholesterol transport by 31%, but not retinol transport. P-Carotene transport was also inhibited by anti-SR-BI, but not by anti-CD36. The inhibitory effects of EZ and anti-SR-BI on P-C transport... 

As demonstrated above, the uptake of [1-C at the apical membrane of differentiated Caco-2 cells occurs via a saturable, facilitated mechanism and is inhibited by Ezetimibe, a clinically used inhibitor of cholesterol absorption. Carotenoids secreted at the basolateral membrane were associated... 

Normen L, Dutta P, Lia A and Andersson H. 2000. Soy sterol esters and 3-sitostanol ester as inhibitors of cholesterol absorption in human small bowel. Am J Clin Nutt 71(4) 908—913. 

This potent inhibitor of cholesterol biosynthesis has been synthesized178 by one-pot esterification of the alcohol 210 with the acid chloride of 2,2-dimethylbutanoic[l-14C] acid, obtained by carbonation of the Grignard reagent prepared from 2-chloro-2-methylbutane (equation 74). Desilylation of 211 afforded [14C]simvastatin 209 in 29% radiochemical yield from 14C-labelled C02. This 14C-labelled drug was needed for elucidation of its metabolic fate in experimental animals. 

De Medina P, Payre BL, Bernad J, Bosser I, Pipy B, Silvente-Poirot S, Favre G, Faye JC, Poirot M (2004b) Tamoxifen is a potent inhibitor of cholesterol esterification and prevents the formation of foam cells. J Pharmacol Exp Ther 308 1165-1173... 

The fact that raising the number of active LDL receptors on liver cells with inhibitors of cholesterol biosynthesis does not decrease Lp(a) concentrations would support this notion (K29, W13). 

Oximes of certain sterols were examined as inhibitors of cholesterol biosynthesis, by suppressing two enzymes that are involved in the biochemical pathway of cholesterol biosynthesis. This dual activity indicates a promising series of biologically reactive oximes (and oxime ethers) capable of reducing cholesterol levels . 

The transformations of 8-hydroxy-a,P-enones to the corresponding internal Michael adducts were performed at 20mol% loading of C9-epi-quinine-thiourea 121 in toluene at increased reaction temperature (50°C) using 3,4,5-trimethoxy-phenylboronic acid for ahphatic and phenylboronic acid for aromatic enones. Under these conditions, this protocol furnished the desired (R)-configured adducts 1-5 in yields ranging from 73 to 86% and ee values of 84—96% (Scheme 6.143) [294]. Product 5 in Scheme 6.143 was identical in all respects with (+)- S)-streptenol A, one of four known streptenols produced by Streptomyces luteogriseus that has attracted attention as an immunostimulant as well as an inhibitor of cholesterol biosynthesis and tumor cells [295]. 

HV158 Qureshi A. A., W. C. Burger, D. M. Peterson, and C. E. Elson. The structure of an inhibitor of cholesterol biosynthesis isolated from barley. J Biol Chem 1986 261(23) 10544-10550. 

Cholesterol lowering drugs are indicated for the prevention and treatment of atherosclerosis. There are three families of these dmgs inhibitors of HMG-CoA reductase (statins), inhibitors of cholesterol transport protein, and inhibitors of cholesteryl ester transfer protein (CETP). They are important drugs from an economical point of view. Among them, several are fluorinated. 

Figure 12 Amyloid cascade hypothesis (modified after Hardy and Selkoe, 2002. Reprinted with permission. American Association for the Advancement of Science) Cholesterol is thouc it to be involved in the formation of f-amyloid (AP) in the brain. Inhibitors of cholesterol formation could then prevent the formation of (neurotoxic) amyloid.

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... 

Normen, L., Dutta, P., Lia, A., and Andersson, H. 2000. Soy sterol esters and beta-sitostanol ester as inhibitors of cholesterol absorption in human small bowel. Am. J. Clin. Nutr. 71, 908-913. Normen, L., Brants, H. A. M., Voorrips, L.E., Andersson, H.A., van den Brandt, P.A., and Gold-bohm, R.A. 2001. Plant sterol intakes and colorectal cancer risk in the Netherlands cohort study on diet and cancer. Am. J. Clin. Nutr. 74, 141-148. 

The material (H) has been tested with preparations of rat liver hepatocytes and has been found to enter them and to serve as an inhibitor of cholesterol biosynthesis therein. Using (H) bearing a specific radiocarbon label, studies have been performed in intact animals. The material has been injected IV and found to be cleared from the blood rapidly, the major portion being delivered to the liver. Small portions are found in bile and intestine, but not in other organs of the animals. 

The most notable discovery in the area of monocyclic azetidin-2-ones is its development as cholesterol absorption inhibitors. The monocyclic azetidin-2-one 559, earlier known as SCH58235, was discovered to have potential cholesterol absorption inhibition property in the late 1990s <1998JME973>. This compound is now in clinical application with the name ezetimibe to treat hypercholesterolemia <2004JME1>. It has been observed recently that the new nonhydrolyzable glycoside 560, prepared using the scaffold of ezetimibe, is also a potent inhibitor of cholesterol absorption <2004AGE4653>. 

Octahydronapthalene synthesis.1 An intramolecular version of this annelation using a Michael addition to a vinyl sulfone provides the octahydronapthalene unit (1) of compactin (2), a mevinic acid of interest as an inhibitor of cholesterol synthesis. 

Lovastatin, commonly known as an inhibitor of cholesterol synthesis, is another agent that has been shown to reduce plasma levels of VLCFA and to increase the ability of X-ALD fibroblasts to metabolize VLCFA. The mechanism for this effect may involve upregulation of ABCD2, which encodes a protein (ALDR) that can substitute for the function of ALDR However, clinical trials with this agent have demonstrated variable reactions, and no clear clinical benefit has been demonstrated. 

The combination of a statin with an inhibitor of cholesterol absorption (e.g., ezetimibe) can lower LDL levels even further. 

Chiral alcohols are useful starting materials for the synthesis of various biologically active compounds. The need for enantiomerically pure drugs and agrochemicals has increased in recent years [13]. Derivatives of enantiopure 1-phenylethanol are important chiral building blocks, which can be used as synthetic intermediates for the production of pharmaceuticals, fine-chemicals agrochemicals, and natural products. In particular (R)-1-phenylethanol is in widespread use as an ophthalmic preservative, an inhibitor of cholesterol intestinal adsorption, a solvatochromic dye, a fragrance, and so on. 

Squalene Final acyclic intermediate in cholesterol synthesis, acts as feedback inhibitor of cholesterol synthesis... 

Hence we study the level of LDL lipoperoxides in patients with atherosclerosis who had been for a long-time treated with HMG-CoA-reductase inhibitors in monotherapy as well as in combination with natural or synthetic antioxidants such as ubiquinon Qio and probucol in double-blind placebo cmitrolled trials [36,37]. The treatment of patients with inhibitor of cholesterol and ubiquinon Qio biosynthesis pravastatine alone in daily dose 40 mg during 6 months was followed by accumulation of LDL lipohydropooxides in the blood plasma [36] (Figure 17). On the other hand the 6 months administration of the same dose of pravastatine in combination with natural antioxidant ubiquinon Qw in daily dose 60 mg sharply decreased even initial LDL lipoperoxides level in the plasma of patients [36] (Figure 17). 

The 4,5-cyclopropanocholestan-3-ols are expected to be inhibitors of cholesterol oxidase. There are two isomers, shown in part as A and B. (Protons pointing up are labeled 3 and protons pointing down are a.) The remainder of the structure is the cholestane skeleton and is not relevant to this problem. The DFQ-COSY and NOESY spectra for both isomers are... 

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