Novel tetrahydrochinoline derived CETP inhibitors

Schmeck, Carsten; Gielen‐Haertwig, Heike; Vakalopoulos, Alexandros; Bischoff, Hilmar; Li, Volkhart; Wirtz, Gabriele; Weber, Olaf

doi:10.1016/j.bmcl.2010.01.071

Cited by 23 publications

(15 citation statements)

References 19 publications

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“…In addition, new compounds are constantly developed and are being tested in their ability to inhibit CETP (Kuo et al ., 2009; Schmeck et al ., 2010; Wang et al ., 2010).…”

Section: Future Therapeutic Optionsmentioning

confidence: 99%

Cardiovascular disease risk reduction by raising HDL cholesterol – current therapies and future opportunities

Ali

Wonnerth

Huber

et al. 2012

British J Pharmacology

247

160

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Since the first discovery of an inverse correlation between high‐density lipoprotein‐cholesterol (HDL‐C) levels and coronary heart disease in the 1950s the life cycle of HDL, its role in atherosclerosis and the therapeutic modification of HDL‐C levels have been major research topics. The Framingham study and others that followed could show that HDL‐C is an independent cardiovascular risk factor and that the increase of HDL‐C of only 10 mg·L−1 leads to a risk reduction of 2–3%. While statin therapy and therefore low‐density lipoprotein‐cholesterol (LDL‐C) reduction could lower coronary heart disease considerably; cardiovascular morbidity and mortality still occur in a significant portion of subjects already receiving therapy. Therefore, new strategies and therapies are needed to further reduce the risk. Raising HDL‐C was thought to achieve this goal. However, established drug therapies resulting in substantial HDL‐C increase are scarce and their effect is controversial. Furthermore, it is becoming increasingly evident that HDL particle functionality is at least as important as HDL‐C levels since HDL particles not only promote reverse cholesterol transport from the periphery (mainly macrophages) to the liver but also exert pleiotropic effects on inflammation, haemostasis and apoptosis. This review deals with the biology of HDL particles, the established and future therapeutic options to increase HDL‐C and discusses the results and conclusions of the most important studies published in the last years. Finally, an outlook on future diagnostic tools and therapeutic opportunities regarding coronary artery disease is given.

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“…In addition, new compounds are constantly developed and are being tested in their ability to inhibit CETP (Kuo et al ., 2009; Schmeck et al ., 2010; Wang et al ., 2010).…”

Section: Future Therapeutic Optionsmentioning

confidence: 99%

Cardiovascular disease risk reduction by raising HDL cholesterol – current therapies and future opportunities

Ali

Wonnerth

Huber

et al. 2012

British J Pharmacology

247

160

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“…BAY 60-5521 is a novel tetrahydrochinoline derived CETP inhibitor with a molecular weight of 503.6 g mol -1 , a calculated pKa value of 5.7 and a log PO/W of 8.8 (partition coefficient, calculated) [20].The compound is practically insoluble in water, sparingly soluble in polyethylene glycol (PEG) and freely soluble in ethanol. Preclinical investigations in transgenic hCETP mice demonstrated that BAY 60-5521 inhibits CETP and elevates serum HDL [21].…”

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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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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“…Among these heterocyclic drugs (e.g., 1 and 2 ; Figure ), the pyridine ring system features prominently and is an essential fragment in medicinal chemistry and drug discovery efforts. Owing to its privileged status, methods for pyridine synthesis or functionalization strategies that enable rational manipulation of potency (e.g., in 4 and 6 ), toxicity (e.g., CYP or hERG inhibition), or other physiochemical properties (e.g., Log P , p K a , lipophilicity) are of immense value. For example, attenuating the metabolism of relatively weak pyridylic C−H bonds (bond dissociation energy (BDE)≈87 kcal mol −1 ) through late‐stage fluorination is particularly appealing.…”

Section: Figurementioning

confidence: 99%

“…For example, attenuating the metabolism of relatively weak pyridylic C−H bonds (bond dissociation energy (BDE)≈87 kcal mol −1 ) through late‐stage fluorination is particularly appealing. Unfortunately, the synthesis of pyridylic fluorides is challenging and relies largely on the introduction of a leaving group at the pyridylic position, followed by fluoride displacement . Thus, despite recent advances in the fluorination of unactivated C(sp 3 )−H bonds, including benzylic C−H, these strategies have not translated broadly to pyridylic fluorination or indeed the fluorination of other heteroarylmethanes, thus limiting their impact in late‐stage lead optimization.…”

Section: Figurementioning

confidence: 99%

A Convenient Late‐Stage Fluorination of Pyridylic C−H Bonds with N‐Fluorobenzenesulfonimide

et al. 2016

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Pyridine features prominently in pharmaceuticals and drug leads,and methods to selectively manipulate pyridine basicity or metabolic stability are highly sought after.Arobust, metal-free direct fluorination of unactivated pyridylic CÀH bonds was developed. This convenient reaction shows high functional-group tolerance and offers complimentary selectivity to existing C À Hf luorination strategies.I mportantly,t his late-stage pyridylic C À Hfluorination provides opportunities to rationally modulate the basicity,l ipophilicity,a nd metabolic stability of alkylpyridine drugs.

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Novel tetrahydrochinoline derived CETP inhibitors

Cited by 23 publications

References 19 publications

Cardiovascular disease risk reduction by raising HDL cholesterol – current therapies and future opportunities

Cardiovascular disease risk reduction by raising HDL cholesterol – current therapies and future opportunities

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

A Convenient Late‐Stage Fluorination of Pyridylic C−H Bonds with N‐Fluorobenzenesulfonimide

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