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      Design, Synthesis, and Biological Evaluation of Benzylamino-Methanone Based Cholesteryl Ester Transfer Protein Inhibitors

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          Abstract

          Cholesteryl ester transfer protein (CETP) is a glycoprotein involved in transporting lipoprotein particles and neutral lipids between high-density lipoprotein (HDL) and low density lipoproteins (LDL) and therefore its a proper target for treating dyslipidemia and related disorders. Guided by our previosuly-reported pharmacophore and QSAR models for CETP inhibition, we synthesized and bioassayed a series of benzylamino-methanones. The most potent illustrated 30% CETP inhibition at 10 μM.

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          Crystal structure of cholesteryl ester transfer protein reveals a long tunnel and four bound lipid molecules.

          R Seddon, P Hensley, Krista Ammirati … (2007)
          Cholesteryl ester transfer protein (CETP) shuttles various lipids between lipoproteins, resulting in the net transfer of cholesteryl esters from atheroprotective, high-density lipoproteins (HDL) to atherogenic, lower-density species. Inhibition of CETP raises HDL cholesterol and may potentially be used to treat cardiovascular disease. Here we describe the structure of CETP at 2.2-A resolution, revealing a 60-A-long tunnel filled with two hydrophobic cholesteryl esters and plugged by an amphiphilic phosphatidylcholine at each end. The two tunnel openings are large enough to allow lipid access, which is aided by a flexible helix and possibly also by a mobile flap. The curvature of the concave surface of CETP matches the radius of curvature of HDL particles, and potential conformational changes may occur to accommodate larger lipoprotein particles. Point mutations blocking the middle of the tunnel abolish lipid-transfer activities, suggesting that neutral lipids pass through this continuous tunnel.
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            Pitfalls in QSAR

            Mark T.D. Cronin, T.Wayne Schultz (2003)
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              Current state and perspectives of 3D-QSAR.

              Miki Akamatsu (2002)
              Quantitative structure-activity relationships (QSAR) have played an important role in the design of pharmaceuticals and agrochemicals. All QSAR techniques assume that all the compounds used in analyses bind to the same site of the same biological target. However, each method differs in how it describes structural properties of compounds and how it finds the quantitative relationships between the properties and activities. The Hansch-Fujita approach, the so-called classical QSAR, is a representative of QSAR methods. Despite the usefulness, classical QSAR techniques cannot be applied to all datasets due to the lack of availability of physicochemical parameters of the whole molecule or its substituents and often it is difficult to estimate those values. In addition, molecular properties based on the three dimensional (3D) structure of compounds may be useful in describing the ligand-receptor interactions. Recently, a variety of ligand-based 3D-QSAR methods such as Comparative Molecular Field Analysis (CoMFA) have been developed and widely used in medicinal chemistry. This review describes different 3D-QSAR techniques and indicates their advantages and disadvantages. Several studies about 3D-QSAR of ADME-toxicity and perspective of 3D-QSAR are also described in this review.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Molecules
                Journal ID (iso-abbrev): Molecules
                Journal ID (publisher-id): molecules
                Title: Molecules
                Publisher: MDPI
                ISSN (Electronic): 1420-3049
                Publication date (Electronic): 19 August 2010
                Publication date Collection: August 2010
                Volume: 15
                Issue: 8
                Pages: 5721-5733
                Affiliations
                Department of Pharmaceutical Sciences, Faculty of Pharmacy, Al-Zaytoonah Private University of Jordan, Amman, Jordan; E-mail: pharmacy@ 123456alzaytoonah.edu.jo
                Author notes
                [* ] Author to whom correspondence should be addressed; E-Mail: reema.abukhalaf@ 123456alzaytoonah.edu.jo or rima_abu_khalaf@ 123456yahoo.com ; Tel.: +962 6 4291511 ext. 239; Fax: +962 6 4291511.
                Article
                Publisher ID: molecules-15-05721
                DOI: 10.3390/molecules15085721
                PMC ID: 6257782
                PubMed ID: 20724961
                SO-VID: dbe3646c-4775-4a5b-861a-a847cb586a0b
                Copyright © © 2010 by the authors;
                License:

                licensee MDPI, Basel, Switzerland. This article is an Open Access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 18 June 2010
                Date revision received : 10 August 2010
                Date accepted : 13 August 2010
                Categories
                Subject: Article

                Keywords: cetp inhibitors,high-density lipoprotein,pharmacophore modeling,quantitative structure-activity relationship,benzylamino-methanones
                Data availability:
                Keywords: cetp inhibitors, high-density lipoprotein, pharmacophore modeling, quantitative structure-activity relationship, benzylamino-methanones

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