Polypharmacology in Drug Discovery

by Peters, Jens-Uwe

Edition: 1st

ISBN13: 9780470590904

ISBN10: 0470590904

Format: Hardcover

Pub. Date: 2012-03-13

Publisher(s): Wiley

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Summary

Polypharmacology can be the two-faced Janus in drug discovery and pharmacology: an adverse, off-target safety risk in some cases or a necessity for effectively treating complex diseases like psychosis and cancer. This book overviews these facets of polypharmacology to help drug discovery researchers both address adverse polypharmacology and approach the discovery of polypharmacological drugs, with a third section of the book uses selected case studies to illustrate drug discovery opportunities. This resource fosters interdisciplinary drug discovery research by guiding researchers in neighboring areas to polypharmacology.

Author Biography

Jens-Uwe Peters, PhD, works in the Medicinal Chemistry Department at F. Hoffmann-La Roche. In his ten years at Roche, he has been involved in numerous drug discovery projects, has contributed to Early Safety Profiling initiatives, and has researched opportunities for polypharmacological drug discovery. Dr. Peters is author or coauthor on twenty-six journal papers and is named on twenty-two patents.

List of contributors
Preface
Introduction: the case for polypharmacology
Polypharmacology - a safety concern in drug discovery
The relevance of off-target polypharmacology
Screening for safety-relevant off-target activities
Introduction
General aspects
Selection of off-targets
In silico approaches to off-target profiling
Summary and conclusions
Pharmacological promiscuity and molecular properties
Introduction: pharmacological promiscuity in the history of drug discovery
Lipophilicity
Molecular weight
Ionisation state
Other molecular descriptors and structural motifs
Implications for drug discovery
Kinases as antitargets in genotoxicity
Protein Kinases and inhibitor-binding sites
Cyclin-Dependent Kinases (CDKs) controlling unregulated cell proliferation
Mitotic kinases as guardians protecting cells from aberrant chromosome segregation
Activity at cardiovascular ion channels: a key issue for drug discovery
Introduction
Screening methods
Structural insights into the interaction between drugs and CV ion channels
Medicinal Chemistry approaches
Conclusion
Prediction of side effects based on fingerprint profiling and data mining
Introduction to BioPrint
The pharmacological fingerprint
Antidepressant example
Profile similarity at non-therapeutic targets
Interpreting the polypharmacology profile
Methods
Patterns of activity
Integrating function profile data with traditional pharmacological binding data
Analysis of the antifungal tioconazole
Conclusions
Polypharmacology - an opportunity for drug discovery
Polypharmacological drugs - "magic shotguns" for psychiatric diseases
Introduction
Definition
The discovery and extent of promiscuity among psychiatric drugs
Why are so many psychiatric drugs promiscuous?
Conclusions
Polypharmacological kinase inhibitors: new hopes for the therapy of cancer
Targeted therapies: a new era in the treatment of cancer
The single-targeted therapy
From single to multi-targeted drugs in cancer therapy
Polypharmacology kinase inhibitors in clinical practice and under development
Concluding remarks
Polypharmacology as an emerging trend in antibacterial discovery
Introduction
Classical antibacterial polypharmacology
New approaches to multi-targeted single pharmacophores
Synthetic lethals
Hybrid molecules
Conclusions
A "magic shotgun" perspective on anticonvulsant mechanisms
Introduction
Anticonvulsant mechanism
Defining promiscuity
Promiscuity: lessons from endogenous signaling
Promiscuity: lessons from anticonvulsant electrophysiology
Use of anticonvulsants in disorders other than epilepsy
Experimental and theoretical support for a "Magic Shotgun" approach
Current multi-target strategies
Practical considerations
Conclusion
Selective Optimization of Side Activities (SOSA): a promising way for drug discovery
Introduction
Definition and principle
Rationale of SOSA
Establishing the SOSA approach
A successful example of the SOSA approach
Other examples of SOSA switches
Discussion
Computer-assisted design using pharmacophores
Conclusions
Selected approaches to polypharmacological drug discovery
Selective multi-targeted drugs
Introduction
Lead Generation
Lead optimization
Case studies
Summary
Computational multitarget drug discovery
Introduction
The pharmacologic hunt of yesteryear
Established technological advancements
Computational drug discovery
Recent technical improvements
Emerging concepts
Summary
Behavior-based screening as an approach to polypharmacological ligands
The Challenges of CNS Drug Discovery
In vivo high throughput screening
Screening libraries of compounds
Relationship between molecular properties and in vivo CNS activity
Following screening hits in secondary assays
Potential therapeutic value of dual adenosine compounds
Summary
Multicomponent Therapeutics
Introduction
Drug synergies are statistically more context dependent
How a synergistic mechanism can lead to therapeutic selectivity
Discussion
Case studies
The discovery of sunitinib as a multitarget treatment of cancer
A brief Introduction to tumor angiogenesis
The discovery of sunitinib: from drug design to first evidences of clinical activity
Pharmacology of sunitinib
Safety of sunitinib
Activity of Sunitinib
Surrogate imaging techniques to capture vascular changes
Surrogate biomarkers
Conclusion
Antipsychotics
Definition and diagnosis of schizophrenia
Etiology and pathophysiology of schizophrenia
Epidemiology
Medical practice and treatment options
Case studies
CATIE
Conclusions
Triple Uptake Inhibitors ("Broad Spectrum" Antidepressants)
Introduction
What is the rationale for developing triple uptake inhibitors as antidepressants?
Preclinical data
Clinical data
Concluding remarks
Therapeutic potential of small molecules modulating the cyclooxygenase and 5-lipoxygenase pathway
Targets of the eicosanoid pathway
Rationale for development of dual inhibitors of the cyclooxygenase and 5-lipoxygenase pathway
Dual inhibitors of the cyclooxygenase and 5-lipoxygenase pathway
Development of Licofelone
Conclusions
Drug research leading to imatinib and beyond to nilotinib
Introduction
Historical background
BCR-ABL1 as the molecular target for CML therapy
Towards antimalarial hybrid drugs
Multitarget drugs for the treatment of Alzheimer's disease
Introduction
Case studies
Conclusions and perspectives
Carbonic anhydrases: off-targets, add-on activities, or emerging novel targets?
Introduction
Carbonic anhydrase inhibition
Topiramate and zonisamide, antiepileptics with potent antiobesity action
Sulfonamide coxibs with antitumor activity due to CA IX/XII inhibition
Sulfamates with steroid sulfatase and carbonic anhydrase inhibitory action as anticancer agents in clinical development
Lacosamide, an antiepileptic with a strange binding mode to Cas
The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian CA isoforms
Conclusions.
Table of Contents provided by Publisher. All Rights Reserved.