Edited by R. Mannhold, H. Buschmann, Jörg Holenz

Editorial Board

G. Folkerts, H. Kubinyi, H. Timmerman, H. van de Waterbeemd, J. Bondo Hansen

Bachhav, Y. (Ed.)

Innovative Dosage Forms

Design and Development at Early Stage

2019

ISBN: 978-3-527-34396-6

Vol. 76

Gervasio, F. L., Spiwok, V. (Eds.)

Biomolecular Simulations in Structure-based Drug Discovery

2018

ISBN: 978-3-527-34265-5

Vol. 75

Sippl, W., Jung, M. (Eds.)

Epigenetic Drug Discovery

2018

ISBN: 978-3-527-34314-0

Vol. 74

Giordanetto, F. (Ed.)

Early Drug Development

2018

ISBN: 978-3-527-34149-8

Vol. 73

Handler, N., Buschmann, H. (Eds.)

Drug Selectivity

2017

ISBN: 978-3-527-33538-1

Vol. 72

Vaughan, T., Osbourn, J., Jalla, B. (Eds.)

Protein Therapeutics

2017

ISBN: 978-3-527-34086-6

Vol. 71

Ecker, G. F., Clausen, R. P., and Sitte, H. H. (Eds.)

Transporters as Drug Targets

2017

ISBN: 978-3-527-33384-4

Vol. 70

Martic-Kehl, M. I., Schubiger, P.A. (Eds.)

Animal Models for Human Cancer

Discovery and Development of Novel Therapeutics

2017

ISBN: 978-3-527-33997-6

Vol. 69

Holenz, Jörg (Ed.)

Lead Generation

Methods and Strategies

2016

ISBN: 978-3-527-33329-5

Vol. 68

There is a great need for new affordable, effective therapeutics for neglected tropical diseases (NTDs). The World Health Organization (WHO) defines NTDs as a diverse group of communicable diseases that prevail in tropical and subtropical conditions – affecting more than one billion people and costing developing economies billions of dollars every year. Populations living in poverty without adequate sanitation and in close contact with infectious vectors and domestic animals and livestock are those worst affected. The designation of “neglected” refers to the limited resources available for controlling and treating these diseases, including the discovery and development of new medicines.

With an eye toward providing a primer to the research community about the various NTDs and challenges in drug discovery for them, this book provides summaries of therapeutic discovery and development efforts for NTDs with a focus on the medicinal chemistry aspects of the programs. The authors for each chapter include experts in medicinal chemistry and biology. Each chapter describes the unmet medical needs, current therapies, available discovery tools including in vitro and in vivo assays and current medicinal chemistry approaches to address unmet medical needs. There are chapters on 10 NTDs as well as 2 emerging viral diseases, Zika and Ebola. The chapter on Zika virus discusses repurposing knowledge from the NTD dengue. We also included an introductory chapter on drug discovery strategies for NTDs.

The aim of drug discovery and development is to identify new medicines to satisfy the unmet medical need of patients. This is easier said than done. Drug discovery and development is very expensive due to the high failure rate of clinical candidates. It is well documented that most candidate medicines will fail, and the cost of failure contributes to the high cost of medicines. The poor efficiency of drug discovery is due in part to the inability to a priori predict if a drug will be efficacious (e.g. will it work or not?). Great advances have been made in reducing attrition due to pharmacokinetics (the ability of the drug to get to the site of action) and safety (toxicity), but not efficacy. The challenge to predicting efficacy is significant due to the complexity of pathophysiology; medicines must account for genetics, molecular mechanisms that translate to specific action as well as the dynamic heterogeneous physiological environment. The only way to confirm efficacy is to evaluate compounds in human proof‐of‐concept studies. These studies are costly in part because prior to the proof‐of‐concept studies, the compounds must be shown to be safe. Because of the high likelihood of failure due to unanticipated toxicity or lack of efficacy, in order to reduce likelihood of project failure, it is necessary to take many (costly!) “shots on goal.”

Therein lies the challenge for drug discovery and development for neglected diseases. The funding is insufficient to support many “shots on goal.” It is important to recognize that there are no fundamental scientific or technological differences between discovery and development for neglected and non‐neglected infectious diseases. What emerges from the chapters in this book is that validated discovery tools are available for the NTDs to support identification of active compounds. These include in vitro assays using the infectious organisms, as well as reliable animal models in most cases.

Not surprisingly, all the contributors identified funding as the most significant liability of their disease area, consistent with the neglected designation. One highly cost‐effective approach to mitigate this is to repurpose knowledge and compounds from other diseases. Repurposing was highlighted in all the chapters as the most logical strategy.

Where funds should be spent is an important question to consider. Should the funds be spent on more knowledge of the fundamental biology hoping that translates to new candidate mechanisms and targets? Or better optimization of candidates to get more viable shots on goal? Or perhaps more repurposing of medicines previously approved for other indications? An apparent advantage of NTDs is the availability of phenotypic screening with models of infected diseases. At first glance, these models should provide good representation of the biology and identify appropriate new mechanisms of action. The limited success in follow‐up on active compounds identified by phenotypic screens begs the questions: Why has there not been more success with actives from phenotypic screens? Do the screening assays not represent the relevant pathological state of the infected organism? Are the candidates not sufficiently optimized for drug‐like properties due to limited medicinal chemistry resources? How much of the efforts are spent revaluating flawed compounds and mechanisms in which the flaws were not reported? The answers to these questions will help ensure that funding is used more efficiently in the future.

What are the opportunities for medicinal chemistry in drug discovery and development for NTDs? Drug discovery and development requires acquisition of disease knowledge, creation or invention of new compounds, and optimization and development of the invention to product. The acquisition of knowledge is the domain of the biologist and funded by government organizations, such as the US National Institutes of Health, while product development involving clinical studies must be funded by pharmaceutical companies or public private partnerships and nonprofit organizations such as Medicines Development for Global Health and the Drugs for Neglected Diseases Initiative. These organizations have been responsible for the recent successes with moxidectin for onchoceriasis and fexinidazole for sleeping sickness. The invention of the new molecule and optimization to a product is the domain of the medicinal chemist. The chapters in this book provide some excellent case studies of the optimization toward clinical candidates. Clearly there is much need and opportunities for medicinal chemists to invent new medicines for NTDs. The challenge is to identify quality starting points and funding sources for the medicinal chemistry optimization.

We acknowledge all the contributing authors for sharing their knowledge and perspectives on neglected tropical diseases. We thank the series editors Gerd Folkers, Hugo Kubinyi, and Raimund Mannhold for the opportunity to address this topic, and Frank Weinreich and Stefanie Volk at Wiley‐VCH for the support and commitment.

The diverse group of neglected tropical diseases (NTDs) prevails in a great many countries with tropical and subtropical conditions [1]. It is estimated that over 1 billion people are infected with NTDs, with a further 1 billion at risk. These diseases are the most common afflictions of the world's poorest people. However, some of the NTDs, such as tuberculosis, affect populations globally, including US populations. NTDs have a terrible impact on health, impede child growth and development, harm pregnant women, and often cause long‐term debilitating illnesses. The fight against NTDs costs developing countries billions of dollars every year. Despite their significance, relatively little financial support has been provided to address NTDs, compared to the burden of ill health that they cause.

Twenty NTDs have been identified and classified by the World Health Organization (WHO). The majority of NTDs has particular characteristics in common [2]:

(i) they preferentially afflict poor people, who lack access to the safe water, sanitation, and basic health services required in order to protect themselves against infection by bacteria, viruses, and other pathogens; (ii) many are chronic; the damage they cause can be irreversible; (iii) NTDs can elicit severe pain and life‐long disabilities; (iv) people with NTDs are often stigmatized and excluded from society, which in turn can affect their mental health.

The infectious agents responsible include the following:

The biological diversity of NTDs means that the control or elimination strategies also are very diverse. The availability of new safe and effective drugs for NTDs could provide public health benefit for overall global health; but because these diseases are found primarily in developing countries, existing incentives have been insufficient to encourage development of new drug therapies. While there are plenty of publications focusing on the large health and economic impact on both the developing and developed world, scientific work dealing with medicinal chemistry aspects of NTDs is less comprehensive. Such work is needed to support the global development programs for discovery and development of new drugs for treatment and prevention or the use of old drugs applying repurposing strategies for tropical disease drug discovery [3]. The importance of supporting such research programs is indicated by the FDA Guidance for Industry, published in 2014 [4]. Thus, to fill this gap, two opinion leaders in this field, David Swinney and Michael Pollastri, accepted our invitation to organize such a volume.

The series editors thank David Swinney and Michael Pollastri for organizing this volume and for working with such excellent authors. Last, but not least, we thank Frank Weinreich and Stefanie Volk from Wiley‐VCH for their valuable contributions to this project and to the entire book series.

References

1. 1 Fenwick, A. (2012). The global burden of neglected tropical diseases. Public Health 126: 233–236.
2. 2 Molyneux, D.H., Savioli, L., and Engels, D. (2017). Neglected tropical diseases: progress towards addressing the chronic pandemic. Lancet 389: 312–325.
3. 3 Klug, D.M., Gelb, M.H., and Pollastri, M.P. (2016). Repurposing strategies for tropical disease drug discovery. Bioorg. Med. Chem. Lett. 26: 2569–2576.
4. 4 Guidance for Industry: Neglected Tropical Diseases of the Developing World: Developing Drugs for Treatment or Prevention, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER), July 2014.