Design and synthesis of potent inhibitors of cholesteryl ester transfer protein (CETP) exploiting a 1,2,3,4-tetrahydroquinoline platform

Rano, Thomas A.; Sieber-McMaster, Ellen; Pelton, Patricia D.; Yang, Maria; Demarest, Keith T.; Kuo, Gee‐Hong

doi:10.1016/j.bmcl.2009.03.051

Cited by 77 publications

(27 citation statements)

References 13 publications

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“…Although potential off-target effects of torcetrapib could have contributed to the failure of this CETP inhibitor [15][16][17], it remains to be demonstrated in the currently ongoing studies with other CETP inhibitors [17][18][19] whether longer-term CETP inhibition has the potential to reduce cardiovascular risk in patients with dyslipidaemia.…”

Section: Figurementioning

confidence: 99%

“…It has been discussed recently whether potential off-target effects of torcetrapib, such as an increase in blood pressure, may have contributed to the failure of this CETP inhibitor [15][16][17], and it has been suggested to continue studying other CETP inhibitors for their potential to improve plasma lipid profiles and reduce cardiovascular risk. Indeed, currently there are several compounds under investigation in preclinical or clinical studies [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein

Boettcher

Heinig

Schmeck

et al. 2012

Brit J Clinical Pharma

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Keywordscholesteryl ester transfer protein, concentration-effect relationship, first in man, pharmacodynamics, pharmacokinetics ---------------------------------------------------------------------- WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesterol esters from the cardioprotective high density lipoprotein cholesterol (HDL-C) to the proatherogenic low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C) leading to lower concentrations of HDL-C but raising the concentrations of proatherogenic LDL-C and VLDL-C. • Inhibition of CETP is considered a potential approach to treat dyslipidaemia.• Phase III studies demonstrating no benefit in regard to the defined clinical end points with the CETP inhibitor torcetrapib challenged the future perspectives of CETP inhibitors as potential therapeutic agents although it has been recently discussed whether potential off-target effects of torcetrapib could have contributed to the failure of this CETP inhibitor.• It has been suggested in recent publications to continue studying other CETP inhibitors for their potential to improve plasma lipid profiles and reduce cardiovascular risk. Currently, several compounds are being investigated in preclinical or clinical studies. WHAT THIS STUDY ADDS• This study provides information on the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of a potential new treatment for dyslipidaemia.• Data from a first in man study with the new CETP inhibitor BAY 60-5521 are presented that demonstrate that BAY 60-5521 is clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL-C could be demonstrated. AIMSTo determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). METHODSThe first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n = 28) or were treated with a placebo (n = 10). RESULTSIn all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relativ...

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Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein

Boettcher

Heinig

Schmeck

et al. 2012

Brit J Clinical Pharma

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“…Various efforts to design novel inhibitors of CETP are ongoing [37,38]. The synthesis of novel tetrahydrochinoline-derived CETP inhibitors has been described [113].…”

Section: Cetp Inhibitorsmentioning

confidence: 99%

Cholesteryl ester transfer protein and its inhibition

Weber

Bischoff

Schmeck

et al. 2010

Cell. Mol. Life Sci.

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Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of cholesteryl esters from the atheroprotective high density lipoprotein (HDL) to the proatherogenic low density lipoprotein cholesterol (LDL) and very low density lipoprotein cholesterol (VLDL) leading to lower levels of HDL but raising the levels of proatherogenic LDL and VLDL. Inhibition of CETP is considered a potential approach to treat dyslipidemia. However, discussions regarding the role of CETP-mediated lipid transfer in the development of atherosclerosis and CETP inhibition as a potential strategy for prevention of atherosclerosis have been controversial. Although many animal studies support the hypothesis that inhibition of CETP activity may be beneficial, negative phase III studies on clinical endpoints with the CETP inhibitor torcetrapib challenged the future perspectives of CETP inhibitors as potential therapeutic agents. The review provides an update on current understanding of the molecular mechanisms involved in CETP activity and its inhibition.

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“…The tetrahydroquinoline framework is considered to be one of the privileged structures in the area of drug discovery, as compounds containing this scaffold display a wide range of biological and pharmaceutical activities [4][5][6][7][8][9][10][11][12], including anti-human immunodeficiency virus (HIV) [13,14], anticancer [15,16], and antimalarial action [17], cholesteryl ester transfer protein inhibition [18], antidiabetic [19] and antifungal activity [20], C 5a receptor antagonism [21], RET tyrosine kinase inhibition [22], etc.…”

Section: Introductionmentioning

confidence: 99%

Bleaching earth clay (pH 12.5)/PEG-400: an efficient recyclable catalytic system for synthesis of 5,6,7,8-tetrahydroquinoline-3-carbonitrile derivatives

et al. 2014

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A green, efficient, and simple method for synthesis of 5,6,7,8-tetrahydroquinoline-3-carbonitrile derivatives via one-pot three-component condensation of 2,6-bis(substituted benzylidene)cyclohexanone, arylamines/substituted 2-aminothiazoles, and malononitrile in the presence of bleaching earth clay pH 12.5 (basic catalyst) as a recyclable and green catalyst in PEG-400 is described. Catalyst recyclability, good to excellent product yield, shorter reaction time, and avoidance of hazardous reagents are the main advantages of this methodology.

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Design and synthesis of potent inhibitors of cholesteryl ester transfer protein (CETP) exploiting a 1,2,3,4-tetrahydroquinoline platform

Cited by 77 publications

References 13 publications

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein

Cholesteryl ester transfer protein and its inhibition

Bleaching earth clay (pH 12.5)/PEG-400: an efficient recyclable catalytic system for synthesis of 5,6,7,8-tetrahydroquinoline-3-carbonitrile derivatives

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