Synthesis and Modeling of Ezetimibe Analogues

Ezetimibe is a well-known drug that lowers blood cholesterol levels by reducing its absorption in the small intestine when joining to Niemann-Pick C1-like protein (NPC1L1). A ligand-based study on ezetimibe analogues is reported, together with one-hit synthesis, highlighted in the study. A convenient asymmetric synthesis of (2S,3S)-N-α-(R)-methylbenzyl-3-methoxycarbonylethyl-4-methoxyphenyl β-lactam is described starting from Baylis–Hillman adducts. The route involves a domino process: allylic acetate rearrangement, stereoselective Ireland–Claisen rearrangement and asymmetric Michael addition, which provides a δ-amino acid derivative with full stereochemical control. A subsequent inversion of ester and acid functionality paves the way to the lactam core after monodebenzylation and lactam formation. It also shows interesting results when it comes to a pharmacophore study based on ezetimibe as the main ligand in lowering blood cholesterol levels, revealing which substituents on the azetidine-2-one ring are more similar to the ezetimibe skeleton and will more likely bind to NPC1L1 than ezetimibe.

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Asymmetric Synthesis of 2,3,6-Trisubstituted Piperidines via Baylis–Hillman Adducts and Lithium Amide through Domino Reaction

Synlett ◽

10.1055/s-0039-1690990 ◽

2019 ◽

Vol 31 (06) ◽

pp. 600-604 ◽

Cited By ~ 1

Author(s):

Mateo M. Salgado ◽

Alejandro Manchado ◽

Carlos T. Nieto ◽

David Díez ◽

Narciso M. Garrido

Keyword(s):

Amino Acid ◽

Asymmetric Synthesis ◽

Claisen Rearrangement ◽

Domino Reaction ◽

Amino Acid Derivative ◽

Side Chain ◽

Lithium Amide ◽

Stereochemical Control ◽

Asymmetric Michael Addition ◽

Polysubstituted Piperidines

A convenient asymmetric synthesis of methyl (2S,3S,6R)-6-(4-fluorophenyl)-2-(4-hydroxyphenyl)-piperidine-3-carboxylate is described, starting from Baylis–Hillman adducts. The route involves a domino process: allylic acetate rearrangement, stereoselective Ireland–Claisen rearrangement and asymmetric Michael addition, which provides a δ-amino acid derivative with full stereochemical control. A subsequent chemoselective transformation of one of the side-chain groups allows an effective cyclization leading to biologically interesting polysubstituted piperidines in which the 2,6-aryl groups could be attached sequentially.

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Effect of intestinal bypass on cholesterol absorption and blood levels in the rabbit

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1964.207.3.567 ◽

1964 ◽

Vol 207 (3) ◽

pp. 567-572 ◽

Cited By ~ 15

Author(s):

Henry Buchwald ◽

Roger L. Gebhard

Keyword(s):

Small Intestine ◽

Ileocecal Valve ◽

Test Dose ◽

Cholesterol Absorption ◽

Blood Cholesterol ◽

Intestinal Bypass ◽

Functional Difference ◽

Cholesterol Levels ◽

Small Intestinal ◽

Blood Radioactivity

A chronic in vivo preparation for the study of cholesterol absorption is described. Ten rabbits which had undergone ileocecal valvuloplasty, ten rabbits subsequent to upper small intestinal bypass and ileocecal valvuloplasty, and ten rabbits with lower small intestinal bypass (including the ileocecal valve), are compared to ten normal controls, on the basis of blood radioactivity, and whole blood cholesterol levels, following a force-fed standard test dose of cholesterol-4-C14, 10 mg, 0.4 µc/mg. The conclusions arrived at from the data are that the entire small intestine is capable of absorbing cholesterol, that bypass of either the upper or the lower half of the small intestine results in a marked (> 80%) reduction in the blood radioactivity subsequent to the oral test dose, and that there is a functional difference between the upper and the lower small intestinal bypass groups. Transit time in the small intestine appears to play a major role in the amount of cholesterol absorbed. To achieve both a marked lowering of cholesterol absorption and circulating cholesterol levels, the most efficacious surgical site of bypass of the small intestine is the ileum.

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New Bioactive Metabolites from a Crown Gall Induced on an Eucalyptus tereticornis Sm. Tree

Zeitschrift für Naturforschung C ◽

10.1515/znc-2013-11-1205 ◽

2013 ◽

Vol 68 (11-12) ◽

pp. 461-470

Author(s):

Maha M. Salama ◽

Shahira M. Ezzat ◽

Riham Salah El Dine ◽

Aly M. El-Sayed ◽

Amany A. Sleem

Keyword(s):

Crown Gall ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Ethanolic Extract ◽

Blood Cholesterol ◽

Amino Acid Derivative ◽

Bioactive Metabolites ◽

Eucalyptus Tereticornis ◽

Cholesterol Levels ◽

New Compounds

Applying a bioactivity-guided isolation strategy for the ethanolic extract of crown gall tumours induced on an Eucalyptus tereticornis tree, two new compounds in addition to a known one were isolated. The new compounds were identified as an amino acid derivative named 1-ethyl-6-(1´-methyl-1´-phenylethyl) piperidin-2-one (1) and a lanostane tetracyclic triterpene named 3β-hydroxy-24-methyllanosta-8,17(20),24(28)-trien-22-oic acid (2), together with stigmasterol-3-O-glucoside (3). The three compounds exhibited significant cytotoxic activity against two human cell lines, breast (MCF7) and colon (HCT116), with IC50 values of 1.01, 1.54, and 2.15 μg/ml, respectively, against MCF7 and 3.49, 3.83, and 3.39 μg/ ml, respectively, against HCT116. Furthermore, in rats elevated levels of blood cholesterol, triglycerides, and low-density lipoprotein (LDLc) were significantly reduced, while the level of high-density lipoprotein (HDLc) was significantly increased by administration of the ethanolic extract as well as of 3. These results support a correlation between the reduction of blood cholesterol levels and improvement of colorectal cancer.

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Electron probe x-ray microanalysis and electron microscopy of amino acid absorption and transport by the small intestine: inhibition by chemical poisons and correlation to the elemental composition of the epithelial cells

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100142311 ◽

1986 ◽

Vol 44 ◽

pp. 134-135

Author(s):

A. J. Tousimis

Keyword(s):

Small Intestine ◽

Amino Acid ◽

Epithelial Cells ◽

Elemental Composition ◽

Isotope Labeling ◽

Structural Components ◽

X Ray ◽

Human Small Intestine ◽

Transport Studies

The elemental composition of amino acids is similar to that of the major structural components of the epithelial cells of the small intestine and other tissues. Therefore, their subcellular localization and concentration measurements are not possible by x-ray microanalysis. Radioactive isotope labeling: I131-tyrosine, Se75-methionine and S35-methionine have been successfully employed in numerous absorption and transport studies. The latter two have been utilized both in vitro and vivo, with similar results in the hamster and human small intestine. Non-radioactive Selenomethionine, since its absorption/transport behavior is assumed to be the same as that of Se75- methionine and S75-methionine could serve as a compound tracer for this amino acid.

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Arginine becomes an essential amino acid after massive resection of rat small intestine.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)31686-7 ◽

1994 ◽

Vol 269 (51) ◽

pp. 32667-32671

Author(s):

Y. Wakabayashi ◽

E. Yamada ◽

T. Yoshida ◽

H. Takahashi

Keyword(s):

Small Intestine ◽

Amino Acid ◽

Essential Amino Acid ◽

Rat Small Intestine ◽

Massive Resection

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Targeting the Cholesterol Paradigm in the Risk Reduction for Atherosclerotic Cardiovascular Disease: Does the Mechanism of Action of Pharmacotherapy Matter for Clinical Outcomes?

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/10742484211023632 ◽

2021 ◽

pp. 107424842110236

Author(s):

Ruihai Zhou ◽

George A. Stouffer ◽

Sidney C. Smith

Keyword(s):

Cardiovascular Disease ◽

Clinical Outcomes ◽

Mechanism Of Action ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Blood Cholesterol ◽

Atherosclerotic Cardiovascular Disease ◽

Pcsk9 Inhibitors ◽

Cholesterol Lowering ◽

Cholesterol Levels

Hypercholesterolemia is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) has been labeled as “bad” cholesterol and high-density lipoprotein cholesterol (HDL-C) as “good” cholesterol. The prevailing hypothesis is that lowering blood cholesterol levels, especially LDL-C, reduces vascular deposition and retention of cholesterol or apolipoprotein B (apoB)-containing lipoproteins which are atherogenic. We review herein the clinical trial data on different pharmacological approaches to lowering blood cholesterol and propose that the mechanism of action of cholesterol lowering, as well as the amplitude of cholesterol reduction, are critically important in leading to improved clinical outcomes in ASCVD. The effects of bile acid sequestrants, fibrates, niacin, cholesteryl ester transfer protein (CETP) inhibitors, apolipoprotein A-I and HDL mimetics, apoB regulators, acyl coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, cholesterol absorption inhibitors, statins, and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, among other strategies are reviewed. Clinical evidence supports that different classes of cholesterol lowering or lipoprotein regulating approaches yielded variable effects on ASCVD outcomes, especially in cardiovascular and all-cause mortality. Statins are the most widely used cholesterol lowering agents and have the best proven cardiovascular event and survival benefits. Manipulating cholesterol levels by specific targeting of apoproteins or lipoproteins has not yielded clinical benefit. Understanding why lowering LDL-C by different approaches varies in clinical outcomes of ASCVD, especially in survival benefit, may shed further light on our evolving understanding of how cholesterol and its carrier lipoproteins are involved in ASCVD and aid in developing effective pharmacological strategies to improve the clinical outcomes of ASCVD.

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