Abstract
Many tumor cells become resistant to commonly used cytotoxic drugs due to the overexpression of ATP-binding cassette (ABC) transporters, namely P-glycoprotein (P-gp). The discovery of the reversal of multidrug resistance (MDR) by verapamil occured in 1981, and in 1968 MDR Chinese hamster cell lines were isolated for the first time. Since then, P-gp inhibitors have been intensively studied as potential MDR reversers. Initially, drugs to reverse MDR were not specifically developed for inhibiting P-gp; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. An example of this first generation P-gp inhibitors is verapamil. The second generation included more specific with less side-effect inhibitors, such as dexverapamil or dexniguldipine. A third generation of P-gp inhibitors comprised compounds such as tariquidar, with high affinity to P-gp at nanomolar concentrations. These generations of inhibitors of P-gp have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate an improvement in therapeutic efficacy. Therefore, new and innovative strategies, such as the fallback to natural products, the design of peptidomimetics and dual activity ligands emerged as a fourth generation of P-gp inhibitors. The chemistry of P-gp inhibitors, as well as their in vitro, in vivo and clinical trials are discussed, and the most recent advances concerning Pgp modulators are reviewed.
Keywords: ATP-binding cassette transporters, blood brain barrier, cancer, cancer stem cells, clinical trials, dual ligands, multidrug resistance, natural products, old drugs, P-glycoprotein, P-gp modulation assays, small molecules inhibitors, structure-activity relationships
Current Medicinal Chemistry
Title:Three Decades of P-gp Inhibitors: Skimming Through Several Generations and Scaffolds
Volume: 19 Issue: 13
Author(s): A. Palmeira, E. Sousa, M. H. Vasconcelos and M. M. Pinto
Affiliation:
Keywords: ATP-binding cassette transporters, blood brain barrier, cancer, cancer stem cells, clinical trials, dual ligands, multidrug resistance, natural products, old drugs, P-glycoprotein, P-gp modulation assays, small molecules inhibitors, structure-activity relationships
Abstract: Many tumor cells become resistant to commonly used cytotoxic drugs due to the overexpression of ATP-binding cassette (ABC) transporters, namely P-glycoprotein (P-gp). The discovery of the reversal of multidrug resistance (MDR) by verapamil occured in 1981, and in 1968 MDR Chinese hamster cell lines were isolated for the first time. Since then, P-gp inhibitors have been intensively studied as potential MDR reversers. Initially, drugs to reverse MDR were not specifically developed for inhibiting P-gp; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. An example of this first generation P-gp inhibitors is verapamil. The second generation included more specific with less side-effect inhibitors, such as dexverapamil or dexniguldipine. A third generation of P-gp inhibitors comprised compounds such as tariquidar, with high affinity to P-gp at nanomolar concentrations. These generations of inhibitors of P-gp have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate an improvement in therapeutic efficacy. Therefore, new and innovative strategies, such as the fallback to natural products, the design of peptidomimetics and dual activity ligands emerged as a fourth generation of P-gp inhibitors. The chemistry of P-gp inhibitors, as well as their in vitro, in vivo and clinical trials are discussed, and the most recent advances concerning Pgp modulators are reviewed.
Export Options
About this article
Cite this article as:
Palmeira A., Sousa E., H. Vasconcelos M. and M. Pinto M., Three Decades of P-gp Inhibitors: Skimming Through Several Generations and Scaffolds, Current Medicinal Chemistry 2012; 19 (13) . https://dx.doi.org/10.2174/092986712800167392
DOI https://dx.doi.org/10.2174/092986712800167392 |
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
-
Mitochondrial Biogenesis: Regulation By Endogenous Gases During Inflammation and Organ Stress
Current Pharmaceutical Design Angiogenesis Inhibitors: Implications for Combination with Conventional Therapies
Current Pharmaceutical Design (Pro)renin Receptor: Pathological Role and Therapeutic Potential in Primary Hypertension
Current Hypertension Reviews Vasorelaxation Caused by Cannabinoids: Mechanisms in Different Vascular Beds
Current Vascular Pharmacology Biology and Therapeutic Applications of Peroxisome Proliferator- Activated Receptors
Current Topics in Medicinal Chemistry Pharmacology and Therapeutic Potential of Sigma1 Receptor Ligands
Current Neuropharmacology The Metabolism of Methazolamide - Identification of Metabolites in Guinea Pig Urine
Drug Metabolism Letters Diabetes and Complications: Cellular Signaling Pathways, Current Understanding and Targeted Therapies
Current Drug Targets Corticosteroids for the Inflammatory Response to Cardiopulmonary Bypass: An Update
Current Pharmaceutical Design Toll-Like Receptors and their Role in Renal Pathologies
Inflammation & Allergy - Drug Targets (Discontinued) Drug Delivery to CNS: Challenges and Opportunities with Emphasis on Biomaterials Based Drug Delivery Strategies
Current Pharmaceutical Design Class IV Antiarrhythmic Agents: New Compounds Using an Old Strategy
Current Pharmaceutical Design Structural Modeling Studies of Aldehyde Dehydrogenase X: Insights into Key Interactions in the Tetrameric Assembly of the Isoenzyme
Protein & Peptide Letters Potential New Targets for Antithrombotic Therapy
Current Pharmaceutical Design Clinical Characteristics and Treatment of Cardiomyopathies in Children
Current Cardiology Reviews ACE2-Ang-(1-7)-Mas Axis in Brain: A Potential Target for Prevention and Treatment of Ischemic Stroke
Current Neuropharmacology Impact of CYP2D6 Genetic Variation on the Response of the Cardiovascular Patient to Carvedilol and Metoprolol
Current Drug Metabolism The Effect of Polyphenol Consumption on Blood Pressure
Mini-Reviews in Medicinal Chemistry Adverse Cardiovascular Effects of Antirheumatic Drugs: Implications for Clinical Practice and Research
Current Pharmaceutical Design Cocaine and Acute Vascular Diseases
Current Drug Abuse Reviews