Abstract
Small molecule inhibitors of KDR kinase activity have typically possessed poor intrinsic physical properties including low aqueous solubility and high lipophilicity. These features have often conferred limited cell permeability manifested in low levels of cell-based KDR inhibitory activity and oral bioavailability. Thus, the design of inhibitors with appropriate physical properties has played a critical role in the development of clinical candidates. We present a variety of structural modifications that have afforded improvements in physical properties and thereby have addressed suboptimal cellular potency and pharmacokinetics for three unique classes of KDR kinase inhibitors.
Keywords: angiogenesis, vascular endothelial growth factor, kdr kinase inhibitors, cellular activity
Current Medicinal Chemistry
Title: Property-Based Design of KDR Kinase Inhibitors
Volume: 11 Issue: 6
Author(s): Mark E. Fraley, William F. Hoffman, Kenneth L. Arrington, Randy W. Hungate, George D. Hartman, Rosemary C. McFall, Kathleen E. Coll, Keith Rickert, Kenneth A. Thomas and Georgia B. McGaughey
Affiliation:
Keywords: angiogenesis, vascular endothelial growth factor, kdr kinase inhibitors, cellular activity
Abstract: Small molecule inhibitors of KDR kinase activity have typically possessed poor intrinsic physical properties including low aqueous solubility and high lipophilicity. These features have often conferred limited cell permeability manifested in low levels of cell-based KDR inhibitory activity and oral bioavailability. Thus, the design of inhibitors with appropriate physical properties has played a critical role in the development of clinical candidates. We present a variety of structural modifications that have afforded improvements in physical properties and thereby have addressed suboptimal cellular potency and pharmacokinetics for three unique classes of KDR kinase inhibitors.
Export Options
About this article
Cite this article as:
Fraley E. Mark, Hoffman F. William, Arrington L. Kenneth, Hungate W. Randy, Hartman D. George, McFall C. Rosemary, Coll E. Kathleen, Rickert Keith, Thomas A. Kenneth and McGaughey B. Georgia, Property-Based Design of KDR Kinase Inhibitors, Current Medicinal Chemistry 2004; 11 (6) . https://dx.doi.org/10.2174/0929867043455729
DOI https://dx.doi.org/10.2174/0929867043455729 |
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
-
Rational Design of Potent and Selective VLA-4 Inhibitors and their Utility in the Treatment of Asthma
Current Topics in Medicinal Chemistry Alkannins and Shikonins: A New Class of Wound Healing Agents
Current Medicinal Chemistry Linking Alzheimer’s Disease and Type 2 Diabetes Mellitus via Aberrant Insulin Signaling and Inflammation
CNS & Neurological Disorders - Drug Targets Penile Rehabilitation After Radical Prostatectomy
Current Drug Targets Current Gastrointestinal Imaging in Children
Current Pediatric Reviews Recent Progress in Discovery and Development of Antimitotic Agents
Anti-Cancer Agents in Medicinal Chemistry Fluorescent Imaging Applications of Quantum Dot Probes
Current Nanoscience Cancer and Aids: New Trends in Drug Design and Chemotherapy
Current Computer-Aided Drug Design Principles and Therapeutic Relevance for Targeting Mitochondria in Aging and Neurodegenerative Diseases
Current Pharmaceutical Design Development of Gene Therapies for Cardiovascular and Renal Diseases by Nucleic Acid Medicines
Medicinal Chemistry Multi-Kinase Inhibitors
Current Medicinal Chemistry Protein Kinase C-theta Inhibitors: A Novel Therapy for Inflammatory Disorders
Current Pharmaceutical Design Recent Developments in the Synthesis of Nicotinic Acetylcholine Receptor Ligands
Current Topics in Medicinal Chemistry PepT1, ASBT-Linked Prodrug Strategy to Improve Oral Bioavailability and Tissue Targeting Distribution
Current Drug Metabolism Inhibition of Disulfide Reductases as a Therapeutic Strategy
Current Enzyme Inhibition Targeting JAK3 Tyrosine Kinase-Linked Signal Transduction Pathways with Rationally-Designed Inhibitors
Anti-Cancer Agents in Medicinal Chemistry Citrus Essential Oils: Current and Prospective Uses in the Food Industry
Recent Patents on Food, Nutrition & Agriculture Pyrrolizidine Alkaloids and their Biological Properties from Indian Heliotropium Species
Current Bioactive Compounds Genes, Environment, Intermediate Phenotypes, and the Pathogenesis of Diabetic Nephropathy
Current Pharmacogenomics Pharmacological Implications of MMP-9 Inhibition by ACE Inhibitors
Current Medicinal Chemistry