Abstract
The therapy of chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) has recently been enriched by the successful launch of the anti-cytokine biologicals Etanercept (tumor necrosis factor (TNF) receptor-p75 Fc fusion protein), Infliximab (chimeric anti-human TNF-α monoclonal antibody), Adalimumab (recombinant human anti-human TNF-α monoclonal antibody) and Anakinra (recombinant form of human interleukin 1β (IL-1) receptor antagonist) [1-3]. The success of these novel treatments has impressively demonstrated the clinical benefit that can be gained from therapeutic intervention in cytokine signalling, highlighting the central role of proinflammatory cytokine systems like IL-1β and TNF-α to be validated targets [4] However, all of the anti-cytokine biologicals available to date are proteins, and therefore suffering to a varying degree from the general disadvantages associated with protein drugs. Therefore, small molecular, orally active anti-cytokine agents, which target specific pathways of proinflammatory cytokines, would offer an attractive alternative to anti-cytokine biologicals. A number of molecular targets have been identified for the development of such small molecular agents but p38 mitogen-activated protein (MAP) kinase occupies a central role in the regulation of IL-1β and TNF-α signalling network at both the transcriptional and translational level [5, 6]. Since the mid-1990s, an immense number of inhibitors of p38 MAP kinase has been characterised in vitro, and to date several compounds have been advanced into clinical trials. This review will highlight the correlation between effective inhibition of p38 MAP kinase at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-α and IL-1β production. SAR will be discussed regarding activity at the enzyme target, but also with regard to properties required for efficient in vitro and in vivo activity.
Keywords: N-Substituted Imidazoles, TNF alpha release, fused heterocycles, crystallisation, cytokine, anilinoquinazoline
Current Topics in Medicinal Chemistry
Title: New Approaches to the Treatment of Inflammatory Disorders Small Molecule inhibitors of p38 MAP Kinase
Volume: 6 Issue: 2
Author(s): Christian Peifer, Gerd Wagner and Stefan Laufer
Affiliation:
Keywords: N-Substituted Imidazoles, TNF alpha release, fused heterocycles, crystallisation, cytokine, anilinoquinazoline
Abstract: The therapy of chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) has recently been enriched by the successful launch of the anti-cytokine biologicals Etanercept (tumor necrosis factor (TNF) receptor-p75 Fc fusion protein), Infliximab (chimeric anti-human TNF-α monoclonal antibody), Adalimumab (recombinant human anti-human TNF-α monoclonal antibody) and Anakinra (recombinant form of human interleukin 1β (IL-1) receptor antagonist) [1-3]. The success of these novel treatments has impressively demonstrated the clinical benefit that can be gained from therapeutic intervention in cytokine signalling, highlighting the central role of proinflammatory cytokine systems like IL-1β and TNF-α to be validated targets [4] However, all of the anti-cytokine biologicals available to date are proteins, and therefore suffering to a varying degree from the general disadvantages associated with protein drugs. Therefore, small molecular, orally active anti-cytokine agents, which target specific pathways of proinflammatory cytokines, would offer an attractive alternative to anti-cytokine biologicals. A number of molecular targets have been identified for the development of such small molecular agents but p38 mitogen-activated protein (MAP) kinase occupies a central role in the regulation of IL-1β and TNF-α signalling network at both the transcriptional and translational level [5, 6]. Since the mid-1990s, an immense number of inhibitors of p38 MAP kinase has been characterised in vitro, and to date several compounds have been advanced into clinical trials. This review will highlight the correlation between effective inhibition of p38 MAP kinase at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-α and IL-1β production. SAR will be discussed regarding activity at the enzyme target, but also with regard to properties required for efficient in vitro and in vivo activity.
Export Options
About this article
Cite this article as:
Peifer Christian, Wagner Gerd and Laufer Stefan, New Approaches to the Treatment of Inflammatory Disorders Small Molecule inhibitors of p38 MAP Kinase, Current Topics in Medicinal Chemistry 2006; 6 (2) . https://dx.doi.org/10.2174/156802606775270323
DOI https://dx.doi.org/10.2174/156802606775270323 |
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
-
Ultrasound Microbubble Contrast and Current Clinical Applications
Recent Patents on Cardiovascular Drug Discovery Towards Retinoid Therapy for Alzheimers Disease
Current Alzheimer Research Glucocorticoids and the Cardiovascular System: State of the Art
Current Pharmaceutical Design Prodrug Designing of NSAIDs
Mini-Reviews in Medicinal Chemistry Regulation of Nociceptive Transmission at the Periphery Via TRPA1-TRPV1 Interactions
Current Pharmaceutical Biotechnology Anti-Nociceptive and Anti-Inflammatory Effects of Stem Bark Extract of <i>Ficus Capensis</i> Thunb (Moraceae) by Bioactivity Fractionation
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Specific Immune Intervention with Monoclonal Antibodies for the Treatment of Multiple Sclerosis
Current Medicinal Chemistry Mechanisms of Improvement of Left Ventricular Function by Intracoronary Human Umbilical Cord-Derived Mesenchymal Stem Cell Infusion in Very Old Patients with Coronary Chronic Total Occlusion
Current Pharmaceutical Design Does Calprotectin Represent a Regulatory Factor in Host Defense or a Drug Target in Inflammatory Disease?
Endocrine, Metabolic & Immune Disorders - Drug Targets From Proteins to Nucleic Acid-Based Drugs: The Role of Biotech in Anti-VEGF Therapy
Anti-Cancer Agents in Medicinal Chemistry Phenylpyazoleanilides as a Potent Inhibitor of IL-15 Dependent T Cell Proliferation. Part 1: A New Class of Orally Available Immunomodulators
Letters in Drug Design & Discovery Autoimmune Fibrotic Adverse Reactions in One-Year Treatment with Cabergoline for Women with Prolactinoma
Endocrine, Metabolic & Immune Disorders - Drug Targets Toll-Like Receptors and Human Disease: Lessons from Single Nucleotide Polymorphisms
Current Genomics An Updated Review for the Diabetic Wound Healing Systems
Current Drug Targets Molecular Imaging Aided Improvement in Drug Discovery and Development
Current Biotechnology Cardiovascular Therapeutics Targets on the NO–sGC–cGMP Signaling Pathway: A Critical Overview
Current Drug Targets Improving of Nutraceutical Features of Many Important Mediterranean Vegetables by Inoculation with a New Commercial Product
Current Pharmaceutical Biotechnology A Comprehensive Study of Pharmacological Behaviors, Nano-Formulations, and Applications of Rosemary
The Natural Products Journal The Carnitine Transporter Network: Interactions with Drugs
Current Chemical Biology Metal-Based Antimicrobial Protease Inhibitors
Current Medicinal Chemistry