Polypharmacology in Drug Discovery

Ed.: Peters, Jens-Uwe

• Gebundenes Buch

Produktbeschreibung

An essential outline of the main facets of polypharmacology in drug discovery research
Extending drug discovery opportunities beyond the "one drug, one target" philosophy, a polypharmacological approach to the treatment of complex diseases is emerging as a hot topic in both industry and academic research. Polypharmacology in Drug Discovery presents an overview of the various facets of polypharmacology and how it can be applied as an innovative concept for developing medicines for treating bacterial infections, epilepsy, cancer, psychiatric disorders, and more. Filled with a collection of instructive case studies that reinforce the material and illuminate the subject, this practical guide:
Covers the two-sided nature of polypharmacology-its contribution to adverse drug reactions and its benefit in certain therapeutic drug classes
Addresses the important topic of polypharmacology in drug discovery, a subject that has not been thoroughly covered outside of scattered journal articles
Overviews state-of-the-art approaches and developments to help readers understand concepts and issues related to polypharmacology
Fosters interdisciplinary drug discovery research by embracing computational, synthetic, in vitro and in vivo pharmacological and clinical aspects of polypharmacology
A clear road map for helping readers successfully navigate around the problems involved with promiscuous ligands and targets, Polypharmacology in Drug Discovery provides real examples, in-depth explanations and discussions, and detailed reviews and opinions to spark inspiration for new drug discovery projects.

Produktdetails

• Verlag: Wiley & Sons
• 1. Auflage
• Seitenzahl: 536
• Erscheinungstermin: 13. März 2012
• Englisch
• Abmessung: 252mm x 164mm x 41mm
• Gewicht: 1066g
• ISBN-13: 9780470590904
• ISBN-10: 0470590904
• Artikelnr.: 33379203

Autorenporträt

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.

Inhaltsangabe

List of contributors. Preface. Introduction: the case for polypharmacology
Andrew L. Hopkins Part A: Polypharmacology - a safety concern in drug
discovery. 1 The relevance of off-target polypharmacology Bruce D. Car 2
Screening for safety-relevant off-target activities Laszlo Urban, Steven
Whitebread, Jacques Hamon, Dmitri Mikhailov and Kamal Azzaoui 2.1
Introduction. 2.2 General aspects. 2.3 Selection of off-targets. 2.4 In
silico approaches to off-target profiling. 2.5 Summary and conclusions. 3
Pharmacological promiscuity and molecular properties Jens-Uwe Peters 3.1
Introduction: pharmacological promiscuity in the history of drug discovery.
3.2 Lipophilicity. 3.3 Molecular weight. 3.4 Ionisation state. 3.5 Other
molecular descriptors and structural motifs. 3.6 Implications for drug
discovery. 4 Kinases as antitargets in genotoxicity Stephan Kirchner 4.1
Protein Kinases and inhibitor-binding sites. 4.2 Cyclin-Dependent Kinases
(CDKs) controlling unregulated cell proliferation. 4.3 Mitotic kinases as
guardians protecting cells from aberrant chromosome segregation. 5 Activity
at cardiovascular ion channels: a key issue for drug discovery Ian M. Bell,
Mark T. Bilodeau and Armando A. Lagrutta 5.1 Introduction. 5.2 Screening
methods. 5.3 Structural insights into the interaction between drugs and CV
ion channels. 5.4 Medicinal Chemistry approaches. 5.5 Conclusion. 6
Prediction of side effects based on fingerprint profiling and data mining
Jacques Migeon 6.1 Introduction to BioPrint. 6.2 The pharmacological
fingerprint. 6.3 Antidepressant example. 6.4 Profile similarity at
non-therapeutic targets. 6.5 Interpreting the polypharmacology profile. 6.6
Methods. 6.7 Patterns of activity. 6.8 Integrating function profile data
with traditional pharmacological binding data. 6.9 Analysis of the
antifungal tioconazole. 6.10 Conclusions. Part B: Polypharmacology - an
opportunity for drug discovery. 7 Polypharmacological drugs - "magic
shotguns" for psychiatric diseases Wesley K. Kroeze and Bryan L. Roth 7.1
Introduction. 7.2 Definition. 7.3 The discovery and extent of promiscuity
among psychiatric drugs. 7.4 Why are so many psychiatric drugs promiscuous?
7.5 Conclusions. 8 Polypharmacological kinase inhibitors: new hopes for the
therapy of cancer Annalisa Petrelli 8.1 Targeted therapies: a new era in
the treatment of cancer. 8.2 The single-targeted therapy. 8.3 From single
to multi-targeted drugs in cancer therapy. 8.4 Polypharmacology kinase
inhibitors in clinical practice and under development. 8.5 Concluding
remarks. 9 Polypharmacology as an emerging trend in antibacterial discovery
Lynn L. Silver 9.1 Introduction. 9.2 Classical antibacterial
polypharmacology. 9.3 New approaches to multi-targeted single
pharmacophores. 9.4 Synthetic lethals. 9.5 Hybrid molecules. 9.6
Conclusions. 10 A "magic shotgun" perspective on anticonvulsant mechanisms
Matt T. Bianchi and Kathy Chuang 10.1 Introduction. 10.2 Anticonvulsant
mechanism. 10.3 Defining promiscuity. 10.4 Promiscuity: lessons from
endogenous signaling. 10.5 Promiscuity: lessons from anticonvulsant
electrophysiology. 10.6 Use of anticonvulsants in disorders other than
epilepsy. 10.7 Experimental and theoretical support for a "Magic Shotgun"
approach. 10.8 Current multi-target strategies. 10.9 Practical
considerations. 10.10 Conclusion. 11 Selective Optimization of Side
Activities (SOSA): a promising way for drug discovery Thierry Langer and
Camille-Georges Wermuth 11.1 Introduction. 11.2 Definition and principle.
11.3 Rationale of SOSA. 11.4 Establishing the SOSA approach. 11.5 A
successful example of the SOSA approach. 11.6 Other examples of SOSA
switches. 11.7 Discussion. 11.8 Computer-assisted design using
pharmacophores. 11.9 Conclusions. Part C: Selected approaches to
polypharmacological drug discovery 12 Selective multi-targeted drugs
Richard Morphy 12.1 Introduction. 12.2 Lead Generation. 12.3 Lead
optimization. 12.4 Case studies. 12.5 Summary. 13 Computational multitarget
drug discovery Jeremy A. Horst, Adrian Laurenzi, Brady Bernard and Ram
Samudrala 13.1 Introduction. 13.2 The pharmacologic hunt of yesteryear.
13.3.Established technological advancements. 13.4.Computational drug
discovery. 13.5.Recent technical improvements. 13.6.Emerging concepts. 13.7
Summary. 14 Behavior-based screening as an approach to polypharmacological
ligands Dani Brunner, Vadim Alexandrov, Barbara Caldarone, Taleen Hanania,
David Lowe, Jeff Schneider and Jayaraman Chandrasekhar 14.1 The Challenges
of CNS Drug Discovery. 14.2 In vivo high throughput screening. 14.3
Screening libraries of compounds. 14.4 Relationship between molecular
properties and in vivo CNS activity. 14.5 Following screening hits in
secondary assays. 14.6 Potential therapeutic value of dual adenosine
compounds. 14.7 Summary. 15 Multicomponent Therapeutics Alexis A. Borisy,
Grant R. Zimmermann and Joseph Lehár 15.1 Introduction. 15.2 Drug synergies
are statistically more context dependent. 15.3 How a synergistic mechanism
can lead to therapeutic selectivity. 15.4 Discussion. Part D: Case studies
16 The discovery of sunitinib as a multitarget treatment of cancer
Catherine Delbaldo, Camelia Colichi, Marie-Paule Sablin, Chantal Dreyer,
Bertrand Billemont, Sandrine Faivre and Eric Raymond 16.1 A brief
introduction to tumor angiogenesis. 16.2 The discovery of sunitinib: from
drug design to first evidences of clinical activity. 16.3 Pharmacology of
sunitinib. 16.4 Safety of sunitinib. 16.5 Activity of Sunitinib. 16.6
Surrogate imaging techniques to capture vascular changes. 16.7 Surrogate
biomarkers. 16.8 Conclusion. 17 Antipsychotics Claus Riemer 17.1 Definition
and diagnosis of schizophrenia. 17.2 Etiology and pathophysiology of
schizophrenia. 17.3 Epidemiology. 17.4 Medical practice and treatment
options. 17.5 Case studies. 17.6 CATIE. 17.7 Conclusions. 18 Triple Uptake
Inhibitors ("Broad Spectrum" Antidepressants) Phil Skolnick 18.1
Introduction. 18.2 What is the rationale for developing triple uptake
inhibitors as antidepressants? 18.3 Preclinical data. 18.4 Clinical data.
18.5 Concluding remarks. 19 Therapeutic potential of small molecules
modulating the cyclooxygenase and 5-lipoxygenase pathway Stefan Laufer and
Wolfgang Albrecht 19.1 Targets of the eicosanoid pathway. 19.2 Rationale
for development of dual inhibitors of the cyclooxygenase and 5-lipoxygenase
pathway. 19.3 Dual inhibitors of the cyclooxygenase and 5-lipoxygenase
pathway. 19.4 Development of Licofelone. 19.5 Conclusions. 20 Drug research
leading to imatinib and beyond to nilotinib Paul W. Manley and Jürg
Zimmermann 20.1 Introduction. 20.2 Historical background. 20.3 BCR-ABL1 as
the molecular target for CML therapy. 21 Towards antimalarial hybrid drugs
Bernard Meunier 22 Multitarget drugs for the treatment of Alzheimer's
disease Andrea Cavalli and Maria Laura Bolognesi 22.1 Introduction. 22.2
Case studies. 22.3 Conclusions and perspectives. 23 Carbonic anhydrases:
off-targets, add-on activities, or emerging novel targets? Claudiu Supuran
23.1 Introduction. 23.2 Carbonic anhydrase inhibition. 23.3 Topiramate and
zonisamide, antiepileptics with potent antiobesity action. 23.4 Sulfonamide
coxibs with antitumor activity due to CA IX/XII inhibition. 23.5 Sulfamates
with steroid sulfatase and carbonic anhydrase inhibitory action as
anticancer agents in clinical development. 23.6 Lacosamide, an
antiepileptic with a strange binding mode to Cas. 23.7 The protein tyrosine
kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian
CA isoforms. 23.8 Conclusions.