Abstract
β-Lactams have recently been identified as potent, highly efficacious cholesterol absorption inhibitors (CAIs). The discovery, SAR, and asymmetric synthesis of this class of hypolipidemic agents are described. Metabolism studies of the first clinical candidate, Sch 48461, led to the identification of a more potent second generation clinical candidate, Sch 58235 (ezetimibe) incorporating key structural elements of the active metabolites. A summary of preclinical and early clinical studies of ezetimibe as monotherapy and in combination with statins is also presented. Efforts to identify a pharmacophore model has led to the development of conformationally constrained analogs and analogs with conformational biases based on intramolecular hydrogen bonding possibilities. Finally, mechanism of action studies have led to the development of many biochemical tools for the investigation and identification of novel proteins involved in cholesterol uptake.
Keywords: actam Cholesterol, ezetimibe, hypolipidemic agents, pharmacophore model, intramolecular hydrogen bonding
Current Medicinal Chemistry
Title: β-Lactam Cholesterol Absorption Inhibitors
Volume: 11 Issue: 14
Author(s): Duane A. Burnett
Affiliation:
Keywords: actam Cholesterol, ezetimibe, hypolipidemic agents, pharmacophore model, intramolecular hydrogen bonding
Abstract: β-Lactams have recently been identified as potent, highly efficacious cholesterol absorption inhibitors (CAIs). The discovery, SAR, and asymmetric synthesis of this class of hypolipidemic agents are described. Metabolism studies of the first clinical candidate, Sch 48461, led to the identification of a more potent second generation clinical candidate, Sch 58235 (ezetimibe) incorporating key structural elements of the active metabolites. A summary of preclinical and early clinical studies of ezetimibe as monotherapy and in combination with statins is also presented. Efforts to identify a pharmacophore model has led to the development of conformationally constrained analogs and analogs with conformational biases based on intramolecular hydrogen bonding possibilities. Finally, mechanism of action studies have led to the development of many biochemical tools for the investigation and identification of novel proteins involved in cholesterol uptake.
Export Options
About this article
Cite this article as:
Burnett A. Duane, β-Lactam Cholesterol Absorption Inhibitors, Current Medicinal Chemistry 2004; 11 (14) . https://dx.doi.org/10.2174/0929867043364865
DOI https://dx.doi.org/10.2174/0929867043364865 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Nanosuspensions as a Versatile Carrier based Drug Delivery System - An Overview
Current Drug Delivery Non Enzymatic Glycated Proteins in the Blood and Cardiovascular Disease
Current Pharmaceutical Design Role of Advanced Glycation End Products (AGEs) in Thrombogenic Abnormalities in Diabetes
Current Neurovascular Research Palladium-Catalyzed Oxyarylation, Azaarylation and α-Arylation Reactions in the Synthesis of Bioactive Isoflavonoid Analogues
Current Organic Synthesis Cardiovascular Complications of Obesity
Current Respiratory Medicine Reviews Cerebrovascular Endothelin Receptor Upregulation in Cerebral Ischemia
Current Vascular Pharmacology HIF Prolyl 4-Hydroxylases and their Potential as Drug Targets
Current Pharmaceutical Design Risk Stratification for Sudden Cardiac Death: Current Approaches and Predictive Value
Current Cardiology Reviews Novel Systemic Drugs for Cutaneous T-Cell Lymphoma
Recent Patents on Anti-Cancer Drug Discovery Antihypertensive Therapy in Children: Differences in Medical Approach Between the United States and Europe
Current Medicinal Chemistry Fructose-1,6-bisphosphatase Inhibitors: A Review of Recent (2000- 2017) Advances and Structure-Activity Relationship Studies
Current Medicinal Chemistry Trimetazidine: Does it Actually Reduce QT Dispersion After First Acute Myocardial Infarction?
Current Drug Therapy Strategy for a Genetic Assessment of Antipsychotic and Antidepressant- Related Proarrhythmia
Current Medicinal Chemistry Pexelizumab, an Anti-C5 Complement Antibody for Primary Coronary Revascularization: A New Insight from Old Versions
Cardiovascular & Hematological Disorders-Drug Targets Neurodevelopmental Delay and Intellectual Disability in Pediatric Heart Transplant
Current Psychiatry Reviews A Brief Review of Cardiovascular Diseases, Associated Risk Factors and Current Treatment Regimes
Current Pharmaceutical Design Targeting Vascular Redox Biology Through Antioxidant Gene Delivery: A Historical View and Current Perspectives
Recent Patents on Cardiovascular Drug Discovery Update on Medical and Surgical Management of Intracerebral Hemorrhage
Reviews on Recent Clinical Trials Antiplatelet Therapies: Aspirin at the Heart of New Directions
Cardiovascular & Hematological Disorders-Drug Targets Total Lipids and Fatty Acid Methyl Esters of Germinated Seeds of Mangrove Wild Legume
Current Nutrition & Food Science