Successful Drug Discovery

János Fischer is a Senior Research Scientist at Richter Plc., Budapest, Hungary. He received his MSc and PhD degrees in organic chemistry from the Eotvos University of Budapest under Professor A. Kucsman. Between 1976 and 1978, he was a Humboldt Fellow at the University of Bonn under Professor W. Steglich. He has worked at Richter Plc. since 1981 where he participated in the research and development of leading cardiovascular drugs in Hungary. His main interest is analogue based drug discovery. He is the author of some 100 patents and scientific publications. Since 2014 he is Chair of the Subcommittee on Drug Discovery and Development of IUPAC. He received an honorary professorship at the Technical University of Budapest. Wayne Childers is Associate Professor of Pharmaceutical Sciences at Temple University, Philadelphia, USA. Wayne received his BA (1979) degree from Vanderbilt University in chemistry and PhD (1984) in organic chemistry from the University of Georgia under the direction of Harold Pinnick. He served as an Assistant Adjunct Professor at Bucknell University before accepting a position as a postdoctoral fellow at the Johns Hopkins University School of Medicine in the laboratories of Dr. Cecil Robinson. He then joined Wyeth Research, Inc., working in numerous therapeutic areas, including psychiatric diseases, stroke, and Alzheimer's disease, and the treatment of chronic pain. He stayed with Wyeth for 22 years, before joining the faculty of Temple University in 2010.

PART I. HDAC Inhibitor Anticancer Drug Discovery

FROM DMSO TO THE ANTICANCER COMPOUND SAHA, AN UNUSUAL INTELLECTUAL PATHWAY FOR DRUG DESIGN
Introduction
The Discovery of SAHA (vorinostat)
Clinical Trials
Follow-On Research - Selective HDAC Inhibitors
Conclusion

ROMIDEPSIN AND THE ZINC-BINDING THIOL FAMILY OF NATURAL PRODUCT HDAC INHIBITORS
Histone Deacetylases as a Therapeutic Target
The Discovery and Development of Romidepsin
The Zinc-Binding Thiol Family of Natural Product HDAC Inhibitors
Synthetic Analogues of the Zinc-Binding Thiol Natural Products
Summary

THE DISCOVERY AND DEVELOPMENT OF BELINOSTAT
Introduction
Discovery of Belinostat
Belinostat Biological Profiling
Formulation Development
Clinical Development
Conclusions

DISCOVERY AND DEVELOPMENT OF FARYDAK (NVP-LBH589, PANOBINOSTAT) AS AN ANTICANCER DRUG
Target Identification: From p21Wafl Induction to HDAC Inhibition
Program Flowchart Assays for Drug Discovery
Hit-To-Lead Campaign: Trichostatin A to LAK974
Lead Optimization: LAK974 to LAQ824
Profiling LAQ824 for Cancer Therapy
Preclinical Development of LAQ824
LAQ824 Follow-Up
Discovery of LBH589
Safety Profile for LBH589
Pan-HDAC Inhibition by LBH589
Cancer Cell-Specific Cytotoxicity of LBH589

DISCOVERY AND DEVELOPMENT OF HDAC SUBTYPE SELECTIVE INHIBITOR CHIDAMIDE: POTENTIAL IMMUNOMODULATORY ACTIVITY AGAINST CANCER
Introduction
Discovery of Chidamide
Molecular Mechanisms of Chidamide
Animal Studies
Clinical Development
Future Perspective

PART II. Steroidal CYP17 Inhibitor Anticancer Drug Discovery

ABIRATERONE ACETATE (ZYTIGA): AN INHIBITOR OF CYP17 AS A THERAPEUTIC FOR CASTRATION-RESISTANT PROSTATE CANCER
Introduction
Discovery and Structure-Activity Relationships (SAR)
Preclinical Characterisation of Abiraterone
Physical Characterisation
Clinical Studies
Conclusion

PART III. Anti-Infective Drug Discoveries

DISCOVERY OF DELAMANID FOR THE TREATMENT OF MULTIDRUG-RESISTANT PULMONARY TUBERCULOSIS
Introduction
Synthesis Strategy
Synthesis Route
Screening Evaluations
Preclinical Data of Delamanid
Clinical Data of Delamanid
Future Priorities and Conclusion

SOFOSBUVIR: THE DISCOVERY OF A CURATIVE THERAPY FOR THE TREATMENT OF HEPATITIS C VIRUS
Introduction
Discussion
Conclusion

PART IV. Central Nervous System (CNS) Drug Discovery

THE DISCOVERY OF THE ANTIDEPRESSANT VORTIOXETINE AND THE RESEARCH THAT UNCOVERED ITS POTENTIAL TO TREAT THE COGNITIVE DYSFUNCTION ASSOCIATED WITH DEPRESSION
Introduction
The Discovery of Vortioxetine
Clinical Development of Vortioxetine for the Treatment of MDD
Uncovering Vortioxetine's Potential to Treat Cognitive Dysfunction in Patients with MDD
Conclusion

PART V. Antiulcer Drug Discovery

DISCOVERY OF VONOPRAZAN FUMARATE (TAK-438) AS A NOVEL, POTENT AND LONG-LASTING POTASSIUM-COMPETITIVE ACID BLOCKER
Introduction
Limitations of PPIs and the Possibility of P-CABs
Exploration of Seed Compounds
Lead Generation from HTS Hit Compound 1
Analysis of SAR and Structure-Toxicity Relationship for Lead Optimization
Selection of Vonoprazan Fumarate (TAK-438) as a Candidate Compound
Preclinical Studiy of TAK-438
Clinical Study of TAK-438
Discussion
Conclusion

PART VI. Cross-Therapeutic Drug Discovery (Respiratory Diseases/Anti-Cancer)

DISCOVERY AND DEVELOPMENT OF NINTEDANIB: A NOVEL ANTIANGIOGENIC AND ANTIFIBROTIC AGENT
Introduction
Structure-Activity Relationships of Oxindole Kinase Inhibitors and the Discovery of Nintedanib
Structural Research
Preclinical Pharmacodynamic Exploration
Nonclinical Drug Metabolism and Pharmacokinetics
Clinical Pharmacokinetics
Toxicology
Phase III Clinical Data
Other Oncology Studies
Conclusions

Index