Progress in Medicinal Chemistry

1st Edition, Volume 52 - January 29, 2013
Editors: G. Lawton, David R. Witty
Language: English
Hardback ISBN:
9 7 8 - 0 - 4 4 4 - 6 2 6 5 2 - 3
Paperback ISBN:
9 7 8 - 0 - 4 4 4 - 6 0 2 4 2 - 8
eBook ISBN:
9 7 8 - 0 - 4 4 4 - 6 2 6 7 1 - 4

Progress in Medicinal Chemistry provides a review of eclectic developments in medicinal chemistry. This volume continues in the serial's tradition of providing an insight into t… Read more

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Progress in Medicinal Chemistry provides a review of eclectic developments in medicinal chemistry. This volume continues in the serial's tradition of providing an insight into the skills required of the modern medicinal chemist; in particular, the use of an appropriate selection of the wide range of tools now available to solve key scientific problems.

Preface
Contributors
Chapter One. Property-Based Design in the Optimisation of Benzamide Glucokinase Activators

1. Introduction
2. Hit-to-Lead SAR—Improving Chemical and Metabolic Stability
3. Balancing Potency, Lipophilicity and Free Drug to Deliver an In Vivo Tool Compound
4. Structural Basis for Small-Molecule Activation
5. Optimising Pharmacokinetics by Focussing on Unbound Clearance
6. Defining a Pharmacokinetic–Pharmacodynamic Relationship
7. Testicular Toxicology and the Role of RAR-α Antagonism
8. Defining Molecular Descriptor Criteria to Improve Success Rates Against Key Optimisation Parameters
9. Overcoming Challenges Associated with Crystallinity and Physical Form
10. Profile of Clinical Candidate AZD1092
11. Risk Mitigation—Remit and Strategy for Backup Campaign
12. Mitigating Fragment Mutagenicity Concerns and Developing a Predictive Model for Ames Activity
13. Moderating H-Bond Donor Count to Improve Absorption
14. Re-balancing Lipophilicity by Incorporation of Polar Heterocycles
15. Identification and Profile of Clinical Candidate AZD1656
16. Synthesis of Benzamide GKAs
17. Summary and Future Perspectives
References

Chapter Two. Medicinal Chemistry of Glucagon-Like Peptide Receptor Agonists

1. Introduction
2. The Incretin Concept and Diabetes
3. Structure–Activity Relationships of the GLP-1 Peptide
4. Exendin-4 and Exenatide
5. Exenatide ER
6. Liraglutide
7. Non-Lipophilic Acid Conjugates
8. Alternative Routes of Administration
9. Inhaled GLP-1 Agonists
10. Alternative Indications
11. Conclusions
References
Further Reading

Chapter Three. Antimalarial Drug Discovery

1. Introduction
2. Antimalarial Drugs Inhibiting Defined Molecular Targets
3. Antimalarial Drugs with a Complex Mode of Action
4. Current Approaches for Antimalarial Lead Discovery
5. New Areas of Investigation for Antimalarial Therapies: Exoerythrocytic Stages
6. Conclusion
References

Chapter Four. Advances in the Discovery of Selective JAK Inhibitors

1. Introduction
2. Biology Background
3. JAK Inhibitors and Progress Towards Subtype Selectivity
4. Structural Biology of the JAK Kinase Family
5. Approved Drugs and Those in Clinical Trial
6. Conclusion
References

Subject Index
Cumulative Index of Authors for Volumes 1–52
Cumulative Index of Subjects for Volumes 1–52

G. Lawton

Dr Geoff Lawton has extensive experience in new medicine discovery across many therapeutic areas in both large and small companies and is a co-inventor of a marketed drug (Cilazapril). He is a former Director of Chemistry at Roche UK, and Vice-president Chemistry and Preclinical Sciences within Roche Bioscience, Palo Alto, USA. He was for five years the research member of a global therapy area strategy planning team for inflammatory diseases, aligning research with the clinical development and marketing parts of the business.

From 2003 to 2007 he was founding Research Director with Lectus Therapeutics building from start-up a drug discovery organisation; generating the team, facilities and project portfolio targeting the next generation of ion channel modulating medicines.

Since 2001 Geoff has provided scientific and strategic evaluation and advice on drug discovery as an independent consultant for a number small and medium sized biotech companies, CROs, VCs, academic groups and medical research charities.

Geoff serves on the Board of Antabio, a French biotech company developing tomorrow’s antibacterial drugs.

He is a founder of INMedD, a new medicines discovery social enterprise.

Affiliations and expertise

St. Ippolyts, Herts, UK

David R. Witty

Dr David Witty has more than 20 years experience in the pharmaceutical industry as a medicinal chemist and project leader working principally in areas of anti-infectives, metabolic diseases, cognition and pain, delivering clinical candidates for several conditions. He led IT Strategy within the Neurology division of GSK, developing and deploying the first Electronic Notebooks for drug discovery to sites in the UK and Singapore. He has contributed more than 90 scientific papers, reviews, patents and books on medicinal and synthetic chemistry.

In 2010 David and several colleagues successfully raised $35M in venture funding to found Convergence Pharmaceuticals, a specialist ion channel company focused on the development of novel treatments for pain, based in Cambridge UK. David presently leads their discovery programme and manages scientific operations within the business.

David is chairman of the Fine Chemicals Group of the Society of Chemical Industry, with responsibility for the delivery of conferences, seminars and training courses for chemists throughout the UK and Europe, and advising parliamentary bodies on matters of relevance to the UK chemical industry.

Since 2008 David has been a STEM ambassador for SETPOINT, introducing school students at both primary and secondary level to the excitement and possibilities of pursuing scientific careers, through workshops, lectures and competitions.

Affiliations and expertise

WITNET LTD, Cambridge, UK

Life sciences

Physical sciences & Engineering

Social sciences & Humanities

Health