ABSTRACT
Restenosis is a complicated disease. Neointima formation and unfavorable remodeling seem to contribute to the development of restenosis after angioplasty. Remodeling, a relatively new hypothesis, might be more crucial than neointima formation, although the two could well be inter-related. Stenting prevents unfavorable remodeling to some extent and lowers restenosis rates as compared to conventional balloon angioplasty. However, restenosis still occurs at too high a rate with stent angioplasty. A great many drugs have been tested in humans for the prevention of restenosis and failed, as most addressed the neointima formation problem only. Future drug design for restenosis should address both remodeling and neointima formation and some antioxidants, such as probucol, have shown promising results in this respect.
Subject(s)
Cardiovascular Agents/therapeutic use , Graft Occlusion, Vascular/prevention & control , Animals , Anticholesteremic Agents/therapeutic use , Anticoagulants/therapeutic use , Heparin/therapeutic use , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Muscle, Smooth, Vascular/drug effects , Platelet Aggregation Inhibitors/therapeutic use , Probucol/therapeutic useABSTRACT
Ezetimibe (Sch-58235) is a cholesterol absorption inhibitor being developed by Schering-Plough for the potential treatment of atherosclerosis and hypercholesterolemia. By January 2000, it was in phase III trials in the US [353762], [363364]. Schering-Plough is studying ezetimibe as a monotherapy for lowering lipid levels and, by February 2000, it was also planning combination studies with commonly used statin (HMG-CoA reductase inhibitor) therapies. The company believes that ezetimibe will have additive effects with the statins, inhibiting the absorption of cholesterol in the intestine while the statins work by inhibiting the production of cholesterol in the liver [363364]. In May 2000, Merck signed an agreement with Schering-Plough to develop and market in the US a once-daily, fixed-combination tablet with simvastatin (Zocor) [368021]. This combination has been shown to improve LDL reduction to 52% as compared to 35% with Zocor alone [375966].
Subject(s)
Anticholesteremic Agents/pharmacology , Azetidines/pharmacology , Drugs, Investigational , Animals , Anticholesteremic Agents/administration & dosage , Anticholesteremic Agents/therapeutic use , Arteriosclerosis/drug therapy , Azetidines/administration & dosage , Azetidines/chemistry , Azetidines/therapeutic use , Bile/metabolism , Cholesterol/metabolism , Cholesterol, LDL/biosynthesis , Clinical Trials, Phase II as Topic , Down-Regulation , Drug Combinations , Drug Evaluation, Preclinical , Drug Therapy, Combination , Ezetimibe , Forecasting , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/drug therapy , Intestinal Absorption/drug effects , Intestinal Mucosa/metabolism , Intestines/drug effects , Molecular Structure , Simvastatin/administration & dosage , Simvastatin/therapeutic useABSTRACT
A series of nitrobenzene compounds has been discovered as potent inhibitors of VCAM-1 expression and, therefore, potential drug candidates for autoimmune and allergic inflammatory diseases. Structure-activity relationship (SAR) studies showed that a nitro group and two other electron-withdrawing groups are essential for these compounds to be potent inhibitors of VCAM-1 expression.
Subject(s)
Intercellular Adhesion Molecule-1/drug effects , Nitrobenzenes/chemical synthesis , Nitrobenzenes/pharmacology , Vascular Cell Adhesion Molecule-1/drug effects , Autoimmune Diseases/drug therapy , Cells, Cultured/cytology , Electron Transport , Endothelium/cytology , Humans , Hypersensitivity/drug therapy , Inflammation/drug therapy , Inhibitory Concentration 50 , Integrin alpha4beta1 , Integrins/metabolism , Receptors, Lymphocyte Homing/metabolism , Structure-Activity Relationship , Vascular Cell Adhesion Molecule-1/biosynthesis , Vascular Cell Adhesion Molecule-1/geneticsABSTRACT
A series of 5-alkyltryptamines (6) and the corresponding conformationally constrained analogues (8) have been synthesized. The structure activity relationships (SAR) at the 5-position of the indole skeleton and the ethylamine side chain have been studied. Functional activities were assessed using isolated rabbit saphenous vein. Potent, selective ligands were found (6e, Ki 2.5 nM, 5-HT1B/5-HT1D 125-fold) that have potential for treating acute migraine.
Subject(s)
Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/pharmacology , Tryptamines/chemistry , Animals , In Vitro Techniques , Protein Binding , Rabbits , Receptor, Serotonin, 5-HT1D , Receptors, Serotonin/metabolism , Saphenous Vein/drug effects , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/metabolism , Tryptamines/metabolismABSTRACT
A series of 5-(2- or 3-thienyl)tryptamine derivatives (9) has been synthesized and shown to be potent and selective 5-HT1D versus 5-HT1B receptor agonists and, therefore, potential treatments for migraine.