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

Abstract 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

Onychomatricoma: a tumor unknown to dermatologists

A sixty-one year old white female was referred to the Dermatology Department to treat an ingrown nail in the inner corner of the left hallux. Examination of the entire nail unit showed the presence of xanthonychia in the outer corner besides thickening and increase in the transverse curvature of the nail plate. Dermoscopy and nuclear magnetic resonance of the free edge of the nail plate detected characteristic signs of onychomatricoma, a diagnosis that was later confirmed by anatomopathological exam.

Inhibición de la proteína de transferencia de ésteres de colesterol para el manejo de la enfermedad cardiovascular ateroesclerótica: el segundo acto "Una esperanza que renace" / Cholesteryl ester transfer protein inhibition in the management of atherosclerotic cardiovascular disease: second act "A rebirth of hope"

Despite the clinical use of statins to reduce serum levels of LDL cholesterol and treat atherosclerotic cardiovascular disease, a high proportion of patients remain at significant residual cardiovascular risk. In this context, low HDL cholesterol levels are an additional risk factor and intervention studies suggest that a fraction of the cardiovascular protection achieved with pharmacotherapy is explained specifically by the increase in serum levels of HDL cholesterol. Pharmacological inhibitors of the cholesteryl ester transfer protein (CETP) can induce a significant elevation in HDL cholesterol and, potentially, lead to better control of residual cardiovascular risk beyond the benefit demonstrated by statins. While the use of torcetrapib had unexpected side effects, dalcetrapib and anacetrapib are new CETP inhibitors with a better safety profile and are currently under study to evaluate their effects on vascular lesions and clinical events in patients at high cardiovascular risk. If these studies show positive findings, we will witness a new biomedical advance as significant as was the clinical.