Cholesteryl Ester Transfer Protein Inhibitory Activity Research Articles

Synthesis, Molecular Modeling and Biological Evaluation of Novel Trifluoromethyl Benzamides as Promising CETP Inhibitors.

Hyperlipidemia is considered a major risk factor for the progress of atherosclerosis. Cholesteryl ester transfer protein (CETP) facilitates the relocation of cholesterol esters from HDL to LDL. CETP inhibition produces higher HDL and lower LDL levels. Synthesis of nine benzylamino benzamides 8a-8f and 9a-9c was performed. In vitro biological study displayed potential CETP inhibitory activity, where compound 9c had the best activity with an IC50 of 1.03 μM. Induced-fit docking demonstrated that 8a-8f and 9a-9c accommodated the CETP active site and hydrophobic interaction predominated ligand/ CETP complex formation. Pharmacophore mapping showed that this scaffold endorsed CETP inhibitors features and consequently elaborated the high CETP binding affinity.

Synthesis and In-Silico Studies of Ortho-Fluorinated Benzenesulfonamides as Putative Anti-CETP Agents

Abstract: Cardiovascular disease is one of the primary causes of death. Atherosclerosis produces artery constriction or obstruction, which can lead to a heart attack or stroke. Cholesteryl Ester Transfer Protein (CETP) is a protein that aids in reverse cholesterol transport. It promotes cholesteryl ester transfer from HDL to LDL and VLDL. So, inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL cholesterol. In this study, ten ortho-fluoro substituted benzenesulfonamides 6a-6j were prepared, and their structure was fully determined using 1H NMR, 13C NMR, HR-MS, and IR. In vitro biological evaluation showed that compound 6d has the highest inhibitory activity with 100% inhibition, while compounds 6a-6c and 6e-6j had activities ranged from 29% - 83% at 10 μM concentration. Interestingly, para-substituted derivatives (6d, 6g, and 6j) were observed to have greater CETP inhibitory activities than their ortho- and meta- analogues irrespective to the nature of substituent, i.e., CH3, Cl, or NO2. Ligandfit docking experiment revealed the difference in the binding mode among the synthesized compounds, which is reflected in their CETP inhibitory activity.

Chemical Synthesis, Biological Evaluation, and Cheminformatics Analysis of a Group of Chlorinated Diaryl Sulfonamides: Promising Inhibitors of Cholesteryl Ester Transfer Protein.

Hyperlipidemia is characterized by an abnormally elevated serum cholesterol, triglycerides, or both. The relationship between an elevated level of LDL and cardiovascular diseases is well-established. Cholesteryl ester transfer protein (CETP) is an enzyme that moves cholesterol esters and triglycerides between LDL, VLDL, and HDL. CETP inhibition leads to a reduction in cardiovascular disease by raising HDL and minimizing LDL. This study synthesized ten meta-chlorinated benzene sulfonamides 6a-6j and explored their structure-activity relationship. The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. Moreover, cheminformatics analyses included pharmacophore mapping, LibDock studies, and cheminformatics characterization using 2-dimensional (2D) molecular descriptors and principal component analysis. Based on in vitro functional CETP assays, compounds 6e, 6i, and 6j demonstrated the strongest inhibitory activities against CETP, reaching 100% inhibition. The inhibitory activity of compounds 6a-6d and 6f-6h ranged from 47.5% to 96.5% at 10 μM concentration. Pharmacophore mapping results suggested CETP inhibitory action, while the docking scores and calculated binding energies predicted favoring binding at the CETP active site. Best-scoring docking poses predicted critical hydrophobic features corresponding to key interactions with His232 and Cys13. Cheminformatics analysis using 2D molecular descriptors indicated that the synthesized compounds span various physicochemical properties and drug-likeness. It was found that a chloro moiety at the ortho-position, or a nitro group at the meta and para-positions, improves the CETP inhibitory activity of synthesized analogs. Computational studies suggest the formation of stable ligand-protein complexes between compounds 6a- 6j and CETP.

Trifluoromethylated Aryl Sulfonamides as Novel CETP Inhibitors: Synthesis, Induced Fit Docking, Pharmacophore Mapping and Subsequent In vitro Validation.

Cardiovascular disease is one of the leading causes of death. Atherosclerosis causes arterial constriction or obstruction, resulting in acute cardiovascular illness. Cholesteryl ester transfer protein (CETP) facilitates reverse cholesterol transport. It supports the transfer of cholesteryl ester from HDL to LDL and VLDL. Inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL. In this study, fourteen trifluoromethyl substituted benzene sulfonamides 6a-6g and 7a-7g were prepared. The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR and HR-MS. They were in vitro tested to estimate their CETP inhibitory activity. In vitro biological evaluation showed that compounds 7d-7f had the highest inhibitory activity with 100% inhibition, while the inhibition observed by compounds 6a-6g, 7a-7c and 7g ranged from 2%-72% at 10 μM concentration. It was found that the addition of a fourth aromatic ring significantly improved the activity, which may be due to the hydrophobic nature of CETP. Also, the presence of ortho-chloro, meta-chloro and para-methyl substituents results in high inhibitory activity. The induced fit docking studies revealed that hydrophobic interaction guided ligand/ CETP binding interaction in addition to H-bond formation with Q199, R201, and H232. Furthermore, pharmacophore mapping demonstrated that this series satisfies the functionalities of the current CETP inhibitors.

Synthesis and Molecular Modeling of Novel 3,5-Bis(trifluoromethyl) benzylamino Benzamides as Potential CETP Inhibitors.

There is an alarming spread of cases of lipid disorders in the world that occur due to harmful lifestyle habits, hereditary risk influences, or as a result of other illnesses or medicines. Cholesteryl Ester Transfer Protein (CETP) is a 476-residue lipophilic glycoprotein that helps in the transport of cholesteryl ester and phospholipids from the atheroprotective HDL to the proatherogenic LDL and VLDL. Inhibition of CETP leads to elevation of HDL cholesterol and reduction of LDL cholesterol and triglycerides; therefore, it is considered a good target for the treatment of hyperlipidemia and its comorbidities. In this research, synthesis, characterization, molecular modeling, and biological evaluation of eight 3,5-bis(trifluoromethyl)benzylamino benzamides 9a-d and 10a-d were carried out. The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and HR-MS. They were biologically tested in vitro to estimate their CETP inhibitory activity. These compounds offered inhibitory effectiveness ranging from 42.2% to 100% at a concentration of 10 μM. Compounds bearing unsubstituted three aromatic rings (9a) or ortho-CF3 substituted (9b) were the most effective compounds among their analogs and showed IC50 values of 1.36 and 0.69 μM, respectively. The high docking scores of 9a-d and 10a-d against 4EWS imply that they might be possible CETP inhibitors. Pharmacophore mapping results demonstrate that the series approves the fingerprint of CETP active inhibitors and therefore explains their high binding affinity against CETP binding site. This work concludes that 3,5-bis(trifluoromethyl)benzylamino benzamides can serve as a promising CETP inhibitor lead compound.

Cholesteryl ester transfer protein inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis

Dyslipidemia is an abnormal lipid profile associated with many common diseases, including coronary heart disease and atherosclerosis. Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that is responsible for the transfer of cholesteryl ester from high-density lipoprotein athero-protective particles to pro-atherogenic very low-density lipoprotein and low-density lipoprotein particles. The requirement for new CETP inhibitors, which block this process has driven our current work. Here, the synthesis as well as the ligand-based and structure-based design of seven oxoacetamido-benzamides 9a-g with CETP inhibitory activity is described. An in vitro study demonstrated that most of these compounds have appreciable CETP inhibitory activity. Compound 9g showed the highest inhibitory activity against CETP with an IC50 of 0.96 μM. Glide docking data for compounds 9a-g and torcetrapib provide evidence that they are accommodated in the CETP active site where hydrophobic interactions drive ligand/CETP complex formation. Furthermore, compounds 9a-g match the features of known CETP active inhibitors, providing a rationale for their high docking scores against the CETP binding domain. Therefore, these oxoacetamido-benzamides show potential for use as novel CETP inhibitors.

2D QSAR studies on a series of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one as CETP inhibitors

ABSTRACT Cardiovascular disease (CVD) is one of the major causes of human death. Preliminary evidence indicates that the inhibition treatment of Cholesteryl Ester Transfer Protein (CETP) causes the most pronounced increase in HDL cholesterol reported so far. Merck has disclosed certain (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]−4-methyl-1,3-oxazolidin-2-one derivatives, which show potent CETP inhibitory activity. Therefore, it would be desirable to develop computational models to facilitate the screening of these inhibitors. In the present work, quantitative structure–activity relationship (QSAR) models have been developed to predict the therapeutic potency of 108 derivatives of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]−4-methyl-1,3-oxazolidin-2-one: Multiple Linear Regression (MLR), Support Vector Regression (SVR) and Feedforward Neural Network using Particle Swarm Optimization (FNN-PSO). Six descriptors were selected using genetic algorithms, whereas, internal and external validation of the models was performed according to all available validation strategies. It was shown that CETP inhibitory activity is mainly governed by electronegativity, the structure of the molecule, and the electronic properties. The best results were obtained with the SVR model. The results obtained may assist in the design of new CETP inhibitors.

Design, Synthesis, and Biological Evaluation of N,N-Disubstituted-4-Arylthiazole-2-Methylamine Derivatives as Cholesteryl Ester Transfer Inhibitors.

Cholesteryl ester transfer protein (CETP) has been identified as a potential target for cardiovascular disease (CVD) for its important role in the reverse cholesteryl transfer (RCT) process. In our previous work, compound 5 was discovered as a moderate CETP inhibitor. The replacement of the amide linker by heterocyclic aromatics and then a series of N,N-substituted-4-arylthiazole-2-methylamine derivatives were designed by utilizing a conformational restriction strategy. Thirty-six compounds were synthesized and evaluated for their CETP inhibitory activities. Structure-activity relationship studies indicate that electron donor groups substituted ring A, and electron-withdrawing groups at the 4-position of ring B were critical for potency. Among these compounds, compound 30 exhibited excellent CETP inhibitory activity (IC50 = 0.79 ± 0.02 μM) in vitro and showed an acceptable metabolic stability.

Molecular Docking and Pharmacophore Modeling Studies of Fluorinated Benzamides as Potential CETP Inhibitors.

Hyperlipidemia is one of the most common chronic diseases worldwide. Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein that facilitates the transfer of cholesteryl ester from the atheroprotective high-density lipoprotein (HDL) to the proatherogenic low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). In this work, synthesis and characterization of five fluorinated 3-benzylamino benzamides 8a-8c, 13a and 13b that target CETP activity were carried out. Benzamides 8b and 8a showed the highest CETP inhibitory activities with an IC50 of 0.75 μM and 4.1 μM respectively. It was found that the presence of p-OCF3 group (as in 8a-8c) enhances CETP inhibitory activity more than p-OCF2CHF2 (as in 13a and 13b) which could be attributed to the bulkiness of the tetrafluoroethoxy group hindering their proper orientation in the binding domain. Additionally m-F derivatives were found to have higher activity against CETP than p-F ones leaving the o-F analogues with the weakest anti-CETP bioactivity. Ligand-based and structure-based drug design strategies confirm that hydrophobic interaction mediates ligand/protein complex formation and explains the activity of our verified molecules.

Fragment-based discovery of novel pentacyclic triterpenoid derivatives as cholesteryl ester transfer protein inhibitors

Cholesteryl Ester Transfer Protein (CETP) is an important therapeutic target for the treatment of atherosclerotic cardiovascular disease. Our molecular modeling study revealed that pentacyclic triterpenoid compounds could mimic the protein-ligand interactions of the endogenous ligand cholesteryl ester (CE) by occupying its binding site. Alignment of the docking conformations of oleanolic acid (OA), ursolic acid (UA) and the crystal conformations of known CETP inhibitor Torcetrapib in the active site proposed the applicability of fragment-based drug design (FBDD) approaches in this study. Accordingly, a series of pentacyclic triterpenoid derivatives have been designed and synthesized as novel CETP inhibitors. The most potent compound 12e (IC50:0.28 μM) validated our strategy for molecular design. Molecular dynamics simulations illustrated that the more stable hydrogen bond interaction of the UA derivative 12e with Ser191 and stronger hydrophobic interactions with Val198, Phe463 than those of OA derivative 12b mainly led to their significantly different CETP inhibitory activity. These novel potent CETP inhibitors based on ursane-type scaffold should deserve further investigation.

Design, synthesis and biological evaluation of novel cholesteryl ester transfer protein inhibitors bearing a cycloalkene scaffold

Cholesteryl ester transfer protein (CETP) is a potential target for cardiovascular disease therapy as inhibition of CETP leads to increased HDL-C in humans. Based on the structure of Merck's biphenyl CETP inhibitor, we designed novel N,N-substituted-cycloalkenyl-methylamine scaffold derivatives by utilizing core replacement and conformational restriction strategies. Consequently, twenty-eight compounds were synthesized and evaluated for their inhibitory activity against CETP. Their preliminary structure-activity relationships (SARs) studies indicate that polar substituents were tolerated in moiety A and hydrophobic alkyl groups at the 5-position of cyclohexene were critical for potency. Among them, compound 17a, bearing an N-(5-pyrazolyl-pyrimidin-2-yl)-cycloalkenyl- methylamine scaffold, exhibited excellent CETP inhibitory activity (IC50 = 0.07 μM) in vitro. Furthermore, it showed an acceptable pharmacokinetic profile in S-D rats and efficient HDL-C increase in high-fat fed hamsters.

2D and 3D QSAR models for identifying diphenylpyridylethanamine based inhibitors against cholesteryl ester transfer protein.

Cholesteryl ester transfer protein (CETP) inhibitors hold promise as new agents against coronary heart disease. Molecular modeling techniques such as 2D-QSAR and 3D-QSAR analysis were applied to establish models to distinguish potent and weak CETP inhibitors. 2D and 3D QSAR models-based a series of diphenylpyridylethanamine (DPPE) derivatives (newly identified as CETP inhibitors) were then performed to elucidate structural and physicochemical requirements for higher CETP inhibitory activity. The linear and spline 2D-QSAR models were developed through multiple linear regression (MLR) and support vector machine (SVM) methods. The best 2D-QSAR model obtained by SVM gave a high predictive ability (R(2)train=0.929, R(2)test=0.826, Q(2)LOO=0.780). Also, the 2D-QSAR models uncovered that SlogP_VSA0, E_sol and Vsurf_DW23 were important features in defining activity. In addition, the best 3D-QSAR model presented higher predictive ability (R(2)train=0.958, R(2)test=0.852, Q(2)LOO=0.734) based on comparative molecular field analysis (CoMFA). Meanwhile, the derived contour maps from 3D-QSAR model revealed the significant structural features (steric and electronic effects) required for improving CETP inhibitory activity. Consequently, twelve newly designed DPPE derivatives were proposed to be robust and potent CETP inhibitors. Overall, these derived models may help to design novel DPPE derivatives with better CETP inhibitory activity.

Novel derivatives of monascus pigment having a high CETP inhibitory activity

The cholesteryl ester transfer protein (CETP), inhibition of which assists in maintaining a high level of high-density lipoprotein cholesterol in the blood, is a target for anti-atherosclerosis treatments. Orange monascus pigment was produced by a Monascus species in a 5 L jar fermenter and various derivative compounds were synthesised by incorporating 19 different l-amino acids into the orange pigment. Among them, the l-Thr and l-Tyr derivatives exhibited high inhibitory activities against the CETP reaction. The inhibitory activities of the l-Thr and l-Tyr derivatives increased in a dose-dependent manner, resulting in IC50 values of 1.0 and 2.3 μM, respectively. When CETP reactions in the presence of the derivatives were performed, the inhibition modes of the l-Thr and l-Tyr derivatives were non-competitive with inhibition constant (Ki) values of 2.7 and 4.3 μM, respectively.

A QSAR classification study on inhibitory activities of 2-arylbenzoxazoles against cholesteryl ester transfer protein

Inhibition of cholesteryl ester transfer protein (CETP) is considered as a new therapy for treating coronary heart disease. Recently, a series of compounds with a 2-arylbenzoxazole skeleton have been identified as potent CETP inhibitors, however, some of them can also be noninhibitors. Therefore, it is highly desirable to have models that can predict whether a compound interacts with CETP. In this work, a quantitative structure–activity relationship study was developed for modeling and classifying CETP inhibitory activity for a dataset of 84 2-arylbenzoxazoles using diverse structural descriptors. The stepwise linear discriminant analysis (LDA) method was then used to explore the best descriptors responsible for inhibitory activity. The LDA and nonlinear support vector machine (SVM) method were employed to establish classification models. These models were strictly validated using internal and external approaches. The SVM model gave the prediction accuracy of 92.65 % on the training set and 81.25 % on the test set, as well as that of the LDA model 82.35 and 75 %. In addition, petitjeanSC, PEOE_VSA_NEG, E_nb, and vsurf_EWmin1 were found to have high correlation with the CETP inhibitory activity. Overall, the SVM model can act as a fast filter for designing new 2-arylbenzoxazoles with better CETP inhibitory activity in future.

Xanthohumol, a prenylated chalcone from Humulus lupulus L., inhibits cholesteryl ester transfer protein

High density lipoprotein (HDL)-cholesterol levels are correlated with a low risk of atherosclerosis. The inhibition of cholesteryl ester transfer protein (CETP), which catalyses cholesterol transfer between lipoproteins, leads to an increase in HDL-cholesterol and is expected to be the next anti-atherogenic target. This study revealed that xanthohumol, a prenylated chalcone, showed the highest inhibition against CETP from screening of natural products in various plants. We investigated the inhibitory activity of some chalcones and flavanones. Naringenin chalcone showed weak CETP inhibition compared with xanthohumol. In addition, isoxanthohumol and naringenin drastically decreased the inhibitory activity. These results suggest that the prenyl group and chalcone structure of xanthohumol were responsible for the CETP inhibitory activity.

English

QSAR studies of thirty 2-arylbenzoxazole derivatives are carried out to probe their inhibitory activity against Cholesteryl Ester Transfer Protein (CETP). QSAR models have been obtained using multiple linear regression (MLR) analysis after manifestation of forward selection algorithm to cull significant descriptors out of descriptor’s pool. QSAR models are elected with adherent set of statistical parameters with R2=0.9431 and R2=0.9069. Validation of modeling includes method of Y-Scrambling and in addition to this, some other methods of validation. Moreover, QSAR approach of 2-arylbenzoxazoles are also attempted, supported and validated by flexible docking studies as well. The search strategies include evolutionary algorithm and edited form of Gehlhaar PLP scoring function. The same set of thirty candidates from 2-arylbenzoxazole derivatives is processed in molecular docking and their docking scores are found in agreement with QSAR studies reported. Remarkable CETP inhibitory activity is exhibited by a 2-arylbenzoxazole derivatives molecule 29C with most comprehensive set of interactions with rerank scores -102.167 and RMSD values 1.104. Hydrogen bond interactions along with hydrophobic and electrostatic interactions are mapped to confirm their potencies.

The conformation and CETP inhibitory activity of [10]-dehydrogingerdione isolated from Zingiber officinale.

In the course of searching for cholesteryl ester transfer protein (CETP) inhibitors from natural sources, a new type of CETP inhibitor, [10]-dehydrogingerdione (1), was isolated from the extract of rhizomes of Zingiber officinale Roscoe. By NMR spectroscopic analysis of its (1)HNMR, (13)C-NMR, and (1)H-(1)H COSY, HMBC, HMQC and NOESY, more precise structure, compared with its originally proposed structures, of [10]-dehydrogingerdione has been elucidated. This active compound inhibited human plasma CETP with IC(50) values of 35 μM.

Chemometric modeling and pharmacophore mapping in coronary heart disease: 2-arylbenzoxazoles as cholesteryl ester transfer protein inhibitors

The plasma concentration of HDL-C and the prevalence of coronary heart disease (CHD) is inversely related. Inhibition of cholesteryl ester transfer protein (CETP) is considered to be a potential approach to treat dyslipidemia and CHD. 2-arylbenzoxazoles were found to be a potential class of CETP inhibitors. A 2D QSAR study was done on a series of 2-arylbenzoxazoles using PCR, PLS and MLR techniques and externally validated to determine significant models. kNN-MFA 3D QSAR was performed on the same series to correlate the effects of electrostatic, steric and hydrophobic parameters with the CETP inhibitory activity using forward backward regression, genetic algorithm and simulated annealing methods. Pharmacophore mapping was also done on the conformers of the 2-arylbenzoxazoles generated by the BEST and the FAST method. This work may provide a platform for generating leads for novel CETP inhibitors.

QSAR study of a series of cholesteryl ester transfer protein inhibitors

Cholesteryl ester transfer protein (CETP), an enzyme which catalyses the transfer of cholesteryl ester from HDL to VLDL, is a promising target for discovery of novel antihyperlipidemic agents due to its pivotal role in HDL metabolism and reverse cholesterol transport. Quantitative structure activity relationship study of a series of CETP inhibitors was carried out using genetic function approximation to study various structural requirements for CETP inhibition. Various lipophilic, electronic, geometric and spatial descriptors were correlated with CETP inhibitory activity. Developed models were found predictive as indicated by their goodr2predvalues and satisfactory internal and external cross-validation results. Study reveals that lipophilicity (ClogP), with parabolic relationship, contributed significantly to the activity along with some electronic, geometric and quantum mechanical descriptors. The present study can be applied to future lead optimization of CETP inhibitors.

Human apoA-I expression in CETP transgenic rats leads to lower levels of apoC-I in HDL and to magnification of CETP-mediated lipoprotein changes

Plasma cholesteryl ester transfer protein (CETP) has a profound effect on neutral lipid transfers between HDLs and apolipoprotein B (apoB)-containing lipoproteins when it is expressed in combination with human apoA-I in HuAI/CETP transgenic (Tg) rodents. In the present study, human apoA-I-mediated lipoprotein changes in HuAI/CETPTg rats are characterized by 3- to 5-fold increments in the apoB-containing lipoprotein-to-HDL cholesterol ratio, and in the cholesteryl ester-to-triglyceride ratio in apoB-containing lipoproteins. These changes occur despite no change in plasma CETP concentration in HuAI/CETPTg rats, as compared with CETPTg rats. A number of HDL apolipoproteins, including rat apoA-I and rat apoC-I are removed from the HDL surface as a result of human apoA-I overexpression. Rat apoC-I, which is known to constitute a potent inhibitor of CETP, accounts for approximately two-thirds of CETP inhibitory activity in HDL from wild-type rats, and the remainder is carried by other HDL-bound apolipoprotein inhibitors. It is concluded that human apoA-I overexpression modifies HDL particles in a way that suppresses their ability to inhibit CETP. An apoC-I decrease in HDL of HuAI/CETPTg rats contributes chiefly to the loss of the CETP-inhibitory potential that is normally associated with wild-type HDL.