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Journal ArticleDOI

Identification of a potent and metabolically stable series of fluorinated diphenylpyridylethanamine-based cholesteryl ester transfer protein inhibitors.

TL;DR: A novel series of diphenylpyridylethanamine-based inhibitors of cholesteryl ester transfer protein is described, and optimization of the urea moiety is explored to balance in vitro metabolic stability with CETP potency in the whole plasma assay.
About: This article is published in Bioorganic & Medicinal Chemistry Letters.The article was published on 2012-10-15. It has received 19 citations till now. The article focuses on the topics: Cholesterylester transfer protein & Sterol O-acyltransferase.
Citations
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Journal ArticleDOI
TL;DR: The effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography are provided, as well as new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds.
Abstract: The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, 18F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in po...

2,149 citations

Journal ArticleDOI
TL;DR: Recent advances regarding the synthetic chemistry of fluorinated aziridine, azetidines, pyrrolidines and their lactam/amino acid counterparts are presented.

119 citations

Journal ArticleDOI
TL;DR: In this article, the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability was examined.
Abstract: Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Molecular weight (MW) is a key parameter in design, and incorporation of fluorine is associated with a disproportionate increase in MW considering the van der Waals radius of fluorine versus hydrogen. Herein we examine a large compound data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-corrected molecular weight (MWFC), where the molecular weight of fluorine has been subtracted, was found to be a more relevant descriptor.

53 citations

Journal ArticleDOI
TL;DR: This perspective will summarize recent events, new research developments, and the discovery of new classes of CETP inhibitors that have advanced to phase 3 cardiovascular outcome clinical trials and been terminated.
Abstract: Cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester and triglycerides between plasma lipoprotein particles HDL and LDL/VLDL, resulting in equilibration between these lipoprotein fractions. Therapy that modulates HDL metabolism to increase HDL-c levels could be an effective strategy to reduce residual cardiovascular risk since it is estimated that for each mg/dL increase in plasma HDL cholesterol, there could be a 2–3% decrease in cardiovascular risk. Modification of the lipoprotein profile by CETP inhibitors is promising, but the beneficial effect of reducing coronary heart disease risk has not yet been proven. To date, four CETP inhibitors have advanced to phase 3 cardiovascular outcome clinical trials, and two have been terminated for off-target adverse effects and lack of efficacy. This perspective will summarize recent events, new research developments, and the discovery of new classes of CETP inhibitors.

31 citations

Journal ArticleDOI
TL;DR: An efficient approach to synthesis of previously unavailable 2-substituted difluorocyclobutane building blocks was developed and applied on a multigram scale and the key step included deoxofluorination of O-protected 2-(hydroxylmethyl)cyclobutanone.
Abstract: An efficient approach to synthesis of previously unavailable 2-substituted difluorocyclobutane building blocks was developed and applied on a multigram scale. The key step of the synthetic sequence...

25 citations

References
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Journal ArticleDOI
TL;DR: Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of my Cardiac Infarction.
Abstract: BACKGROUND Lowering the blood cholesterol level may reduce the risk of coronary heart disease. This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease. METHODS We randomly assigned 6595 men, 45 to 64 years of age, with a mean (+/- SD) plasma cholesterol level of 272 +/- 23 mg per deciliter (7.0 +/- 0.6 mmol per liter) to receive pravastatin (40 mg each evening) or placebo. The average follow-up period was 4.9 years. Medical records, electrocardiographic recordings, and the national death registry were used to determine the clinical end points. RESULTS Pravastatin lowered plasma cholesterol levels by 20 percent and low-density-lipoprotein cholesterol levels by 26 percent, whereas there was no change with placebo. There were 248 definite coronary events (specified as nonfatal myocardial infarction or death from coronary heart disease) in the placebo group, and 174 in the pravastatin group (relative reduction in risk with pravastatin, 31 percent; 95 percent confidence interval, 17 to 43 percent; P < 0.001). There were similar reductions in the risk of definite nonfatal myocardial infarctions (31 percent reduction, P < 0.001), death from coronary heart disease (definite cases alone: 28 percent reduction, P = 0.13; definite plus suspected cases: 33 percent reduction, P = 0.042), and death from all cardiovascular causes (32 percent reduction, P = 0.033). There was no excess of deaths from noncardiovascular causes in the pravastatin group. We observed a 22 percent reduction in the risk of death from any cause in the pravastatin group (95 percent confidence interval, 0 to 40 percent; P = 0.051). CONCLUSIONS Treatment with pravastatin significantly reduced the incidence of myocardial infarction and death from cardiovascular causes without adversely affecting the risk of death from noncardiovascular causes in men with moderate hypercholesterolemia and no history of myocardial infarction.

7,099 citations

Journal Article
TL;DR: Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations.

6,614 citations

Journal ArticleDOI
27 May 1998-JAMA
TL;DR: Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL- C levels and supports the inclusion of HDL-C in risk-factor assessment and the need for reassessment of the National Cholesterol Program guidelines.
Abstract: 0.63; 95% confidence interval [CI], 0.50-0.79;P,.001), myocardial infarction (95 vs 57 myocardial infarctions; RR, 0.60; 95% CI, 0.43-0.83; P = .002), unstable angina (87 vs 60 first unstable angina events; RR, 0.68; 95% CI, 0.49-0.95;P = .02), coronary revascularization procedures (157 vs 106 procedures; RR, 0.67; 95% CI, 0.520.85; P = .001), coronary events (215 vs 163 coronary events; RR, 0.75; 95% CI, 0.61-0.92; P = .006), and cardiovascular events (255 vs 194 cardiovascular events; RR, 0.75; 95% CI, 0.62-0.91; P = .003). Lovastatin (20-40 mg daily) reduced LDL-C by 25% to 2.96 mmol/L (115 mg/dL) and increased HDL-C by 6% to 1.02 mmol/L (39 mg/dL). There were no clinically relevant differences in safety parameters between treatment groups. Conclusions.— Lovastatin reduces the risk for the first acute major coronary event in men and women with average TC and LDL-C levels and below-average HDL-C levels. These findings support the inclusion of HDL-C in risk-factor assessment, confirm the benefit of LDL-C reduction to a target goal, and suggest the need for reassessment of the National Cholesterol Education Program guidelines regarding pharmacological intervention.

5,301 citations

Journal ArticleDOI
TL;DR: The major potent lipid risk factor was HDL cholesterol, which had an inverse association with the incidence of coronary heart disease in either men or women and these associations were equally significant even when other lipids and other standard risk factors for coronaryHeart disease were taken into consideration.

5,054 citations

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