Abstract
In the area of lead optimization for potential CNS-active drugs in medicinal chemistry, there is a great need for experimental methodologies that can generate data relevant to estimates of free (unbound) drug exposure within the CNS. The methods chosen have to be efficient and have to measure a pharmacologically relevant entity. The lack of methods for generating such data is probably linked with the lack of successful lead optimization strategies within CNS drug discovery. This article evaluates available methods for estimating drug delivery to the brain, and discusses the relevance of the methods from the perspective of CNS exposure to free drug. It is suggested that the extent of drug delivery is the most important investigative parameter, since permeability (rate of transfer) can vary within a relatively wide range and still allow effects within the CNS. Following this suggestion would shift the focus from the current way of thinking and could lead to the development of less lipophilic compounds than are currently being investigated. It is concluded that an extensive collection of quality data on brain drug delivery, transporter affinities and in vivo behavior is urgently required so as to be able to build relevant predictive in vitro and in silico models for the future. These models need to be much more focused on the asymmetry of active transport across the BBB than on permeability data.
Current Topics in Medicinal Chemistry
Title: Methodologies to Assess Brain Drug Delivery in Lead Optimization
Volume: 9 Issue: 2
Author(s): Margareta Hammarlund-Udenaes, Ulf Bredberg and Markus Friden
Affiliation:
Abstract: In the area of lead optimization for potential CNS-active drugs in medicinal chemistry, there is a great need for experimental methodologies that can generate data relevant to estimates of free (unbound) drug exposure within the CNS. The methods chosen have to be efficient and have to measure a pharmacologically relevant entity. The lack of methods for generating such data is probably linked with the lack of successful lead optimization strategies within CNS drug discovery. This article evaluates available methods for estimating drug delivery to the brain, and discusses the relevance of the methods from the perspective of CNS exposure to free drug. It is suggested that the extent of drug delivery is the most important investigative parameter, since permeability (rate of transfer) can vary within a relatively wide range and still allow effects within the CNS. Following this suggestion would shift the focus from the current way of thinking and could lead to the development of less lipophilic compounds than are currently being investigated. It is concluded that an extensive collection of quality data on brain drug delivery, transporter affinities and in vivo behavior is urgently required so as to be able to build relevant predictive in vitro and in silico models for the future. These models need to be much more focused on the asymmetry of active transport across the BBB than on permeability data.
Export Options
About this article
Cite this article as:
Hammarlund-Udenaes Margareta, Bredberg Ulf and Friden Markus, Methodologies to Assess Brain Drug Delivery in Lead Optimization, Current Topics in Medicinal Chemistry 2009; 9 (2) . https://dx.doi.org/10.2174/156802609787521607
DOI https://dx.doi.org/10.2174/156802609787521607 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
-
Antiviral Drug Discovery Targeting to Viral Proteases
Current Pharmaceutical Design Fluoxetine Improves Behavioral Performance by Suppressing the Production of Soluble β-Amyloid in APP/PS1 Mice
Current Alzheimer Research Targeted Multimodal Liposomes for Nano-delivery and Imaging: An Avenger for Drug Resistance and Cancer
Current Gene Therapy <i>Ralstonia Mannitolilytica</i>, an Unusual Pathogen in the Neonatal Intensive Care Unit: A Case of Neonatal Sepsis and Literature Review
Infectious Disorders - Drug Targets Impact of HIV on Regional & Cellular Organisation of the Brain
Current HIV Research Inflammation as a Therapeutic Target in Acute Ischemic Stroke Treatment
Current Topics in Medicinal Chemistry Potential Therapeutic Application of Chondroitin Sulfate/Dermatan Sulfate
Current Drug Discovery Technologies Current and Future Therapies Targeting the Immune System in Multiple Sclerosis
Current Pharmaceutical Biotechnology Editorial [Revisiting the Paris Declaration: Pharmacogenomics and Personalized Medicine as Accelerators for Development Aid and Effectiveness]
Current Pharmacogenomics and Personalized Medicine Pathophysiogenesis of Mesial Temporal Lobe Epilepsy: Is Prevention of Damage Antiepileptogenic?
Current Medicinal Chemistry Association of Genetic Variation with Pneumonia
Current Respiratory Medicine Reviews Aquaporin and Vascular Diseases
Current Neuropharmacology Aligning Animal Models of Clinical Germinal Matrix Hemorrhage, From Basic Correlation to Therapeutic Approach
Current Drug Targets Potential Antibacterial Activity of Yemeni Sidr Honey Against <i>Pseudomonas aeruginosa</i> and <i>Streptococcus pyogenes</i>
Anti-Infective Agents Chemistry and Pharmacology of Natural Catechins from <i>Camellia sinensis</i> as Anti-MRSA Agents
Current Topics in Medicinal Chemistry Driving Cellular Plasticity and Survival Through the Signal Transduction Pathways of Metabotropic Glutamate Receptors
Current Neurovascular Research The Challenge of Counterfeit Drugs: A Comprehensive Review on Prevalence, Detection and Preventive Measures
Current Drug Safety Neonatal Systemic Thrombosis: An Updated Overview
Current Vascular Pharmacology Treatment of Viral Encephalitis
Central Nervous System Agents in Medicinal Chemistry Antimicrobial Proteins from Snake Venoms: Direct Bacterial Damage and Activation of Innate Immunity Against Staphylococcus aureus Skin Infection
Current Medicinal Chemistry