Neglected Diseases and Drug Discovery: Rsc: Volume 14 (Drug Discovery Series) - Hardcover

Hardcover

ISBN 10: 1849731926 ISBN 13: 9781849731928

Publisher: Royal Society of Chemistry, 2011

Synopsis

An invaluable guide to successful practice in neglected tropical diseases (NTDs) and highlights best practice to guide the ongoing drug discovery effort.

About this title

About the Author

Medicinal Chemistry Consultant, UK

From the Back Cover

There are 8 million deaths every year from neglected tropical diseases (NTDs) in the underdeveloped world, whilst drug discovery focus and practice is only recently taking on greater urgency and embracing the latest technologies. The aim of this book is to present a state-of-the-art review of drug discovery in respect of NTDs and to highlight best practice to guide ongoing drug discovery effort, to raise awareness and promote debate in neglected disease areas that still have unmet medical need. Neglected Diseases and Drug Discovery, details nearly all of the key diseases that fall into this class. It sets out to make a critical appraisal of ongoing research with a focus on the key science that has led to breakthroughs, especially from a medicinal chemistry perspective. The book covers in great depth current efforts in the malaria, trypanosomatid, flavivirus and tuberculosis fields, wherein an upsurge in research efforts has been evident in recent times. Additionally, there is some focus on the 'neglected' neglected diseases, notably diarrhea, helminths, HIV (in worldwide terms) and lower respiratory tract infections. In respect of the more publicised disease areas such as malaria there is a review of each disease and established compounds, mechanistic classes and new horizons. In the more under-publicised areas the chapters seek to highlight the pressing need for better and more widely available treatments Written by a team of experienced experts the book will prove to be an invaluable guide to successful practice in NTDs highlighting ongoing and new drug discovery efforts in this field. It will aid both researchers and the general reader, by summarising the key learning to date and provide a clear overview of the challenges that remain.

Excerpt. © Reprinted by permission. All rights reserved.

Neglected Diseases and Drug Discovery

By Michael J. Palmer, Timothy N. C. Wells

The Royal Society of Chemistry

Copyright © 2012 Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-84973-192-8

Contents

Chapter 1 Malaria: New Medicines for its Control and Eradication Timothy N. C. Wells and Winston E. Gutteridge, 1, 
Chapter 2 Semisynthetic Artemisinin and Synthetic Peroxide Antimalarials Leann Tilley, Susan A. Charman and Jonathan L. Vennerstrom, 33, 
Chapter 3 Antimalarial Agents Targeting Nucleotide Synthesis and Electron Transport: Insight from Structural Biology Margaret A. Phillips, 65, 
Chapter 4 Human Targets Repositioning and Cell-based Approaches for Antimalarial Discovery Arnab K. Chatterjee and Elizabeth A. Winzeler, 88, 
Chapter 5 The Medicinal Chemistry of Eradication: Hitting the Lifecycle where it Hurts. Approaches to Blocking Transmission Jeremy Nicholas Burrows and Robert Edward Sinden, 112, 
Chapter 6 Drugs for Kinetoplastid Diseases – Current Situation and Challenges Simon L. Croft, 134, 
Chapter 7 Drug Discovery for Kinetoplastid Diseases Robert T. Jacobs, 159, 
Chapter 8 The Challenges of Flavivirus Drug Discovery Pei-Yong Shi, Qing-Yin Wang and Thomas H. Keller, 203, 
Chapter 9 Current Approaches to Tuberculosis Drug Discovery and Development Mark J. Mitton-Fry and Debra Hanna, 228, 
Chapter 10 Diarrhoeal Diseases David Brown, 262, 
Chapter 11 Anthelmintic Discovery for Human Infections Timothy G. Geary and Noelle Gauvry, 290, 
Chapter 12 Managing the HIV Epidemic in the Developing World – Progress and Challenges Elna van der Ryst, Michael J Palmer and Cloete van Vuuren, 322, 
Chapter 13 Drug Discovery for Lower Respiratory Tract Infections J Carl Craft, 366, 
Subject Index, 412, 

CHAPTER 1

Malaria: New Medicines for its Control and Eradication

1.1 Introduction

Malaria is caused by protozoan parasites of the genus Plasmodium that infect and destroy red blood cells, leading to fever, severe anaemia and, if untreated, cerebral malaria and death. Plasmodium falciparum is the dominant species in sub-Saharan Africa, and is responsible for almost one million deaths each year. The disease burden is heaviest in sub-Saharan African children under 3 years old (who have frequent attacks and little immunological protection), and also in expectant mothers. Malaria is both a cause and a consequence of poverty: in countries with intense malaria transmission, the economic impact of the disease results in a slowing of economic growth of 1.3% per year, translating to a reduction of the Gross Domestic Product in sub-Saharan Africa estimated to be US$12 billion per year.

The global fight to control malaria requires a multifaceted approach. At present, we have a wide range of effective tools. Medicines can be used to prevent as well as to cure, especially in vulnerable populations such as infants or pregnant women. Insecticides and larvicide spraying and the use of insecticide-impregnated bed nets to protect against infection by mosquitoes have dramatically increased in recent years. This success brings with it the need for the development of the next generation of insecticides, since resistance to the current gold standard, the pyrethroids, is already an issue. Developing a vaccine is proving especially challenging, as the parasite has sophisticated mechanisms for avoiding the host immune system. The best candidate currently is GSK 257049, known as RTS,S/AS202, where phase III trials are expected to finish in July 2013. Phase II studies suggest that it will reduce risk of clinical malaria, and decrease mortality in severe malaria by 50%.

In November 2007, the Bill and Melinda Gates Foundation set an agenda with the final goal of completely eradicating malaria, an objective supported by both the World Health Organization (WHO) and its Roll Back Malaria (RBM) partnership. Commentators have described this objective as 'worthy, challenging, and just possible', but one which must be pursued with balance, humility, and rigorous analysis.

The addition of this new goal has implications for the global malaria R&D agenda, which have been discussed in a variety of different working groups. Future antimalarial medicines must not only be able to treat the asexual blood stages of P. falciparum, but also to block the transmission of the parasite to other persons via the mosquito vector and, in the case of P. vivax infection, to target the dormant liver-stage of the parasite. In this chapter, we discuss the current pipeline of antimalarial medicines, and the target product profiles for the generation of such products.

1.2 The Challenges of the Different Plasmodium Species

Four main species of the malaria parasite infect humans. P. falciparum is responsible for the vast majority of the malaria-linked deaths in sub-Saharan Africa and is therefore the most important target. P. vivax constitutes as much as 25–40% of the global malaria burden, particularly in South and Southeast Asia, and Central and South America. It does not normally progress to cerebral malaria, and has been traditionally labelled benign. However, P. vivax causes a greater host inflammatory response than P. falciparum at equivalent parasitaemia. Mortality from P. vivax is most likely underreported, as recent analyses in Papua (Indonesia), have shown similar mortality figures in children to those found with P. falciparum.

Medicines that are active on the asexual erythrocyte stages of P. falciparum, such as the artemisinin-based combination therapies (ACTs), are assumed to be fully active against the other species. The formal clinical database supporting this assumption is relatively thin but is well supported by empirical observation. Historically, mixed infections of P. falciparum and P. vivax are rarely reported, possibly because P. falciparum suppresses the development of P. vivax, but PCR detection methods have shown that these can be as high as 30%.14 The other two species are P. malariae and P. ovale. Currently, these are diagnosed by microscopy, and represent a small percentage of infections. Diagnosis based on Polymerase Chain Reaction (PCR) will undoubtedly lead to a re-evaluation of the presence of mixed infections, since it is able to quantify low parasite numbers, and is often more definitive as a diagnostic.

From a treatment and eradication perspective, there are 3 key differences between the species. The first difference occurs in the liver. Following infection of the patient, parasites rapidly progress to infect hepatocytes, undergo asexual schizogony, and release large numbers of merozoites into the host bloodstream. In P. vivax and P. ovale, some of the liver parasites become dormant (a form known as the hypnozoite). These forms can be reactivated after periods that vary from 3 weeks to several years, dependent on the strain of parasite and the status of the host. Unless the hypnozoites are eliminated, malaria will continue to relapse periodically. Since P. vivax transmission is rarely intense, activation of hypnozoites is thought to be a major contributor to disease frequency.

The second difference between the species is in the time taken for the parasite to replicate in the host. The time between febrile paroxysms varies from around 48 hours for P. falciparum and P. vivax to 72 hours for the more benign P. malariae. There has been a recent interest in a fifth species, P. knowlesi, a parasite of Old World monkeys, now known to infect humans. PCR methods show that it is often misdiagnosed as P. malariae infection, which is usually uncomplicated and has low parasitaemia. However, P. knowlesi replicates every 24 h, and so is potentially life-threatening if not treated expeditiously. Therapeutically, the challenge in this case is to have a therapy with a rapid onset of action.

Third is the timing of the appearance of gametocytes in the blood stream. In P. falciparum, the gametocytes do not appear until several days after the initial parasitaemia and fever, whereas in P. vivax they appear concurrently or even before asexual parasites. An ideal treatment for blood stages of P. vivax must be able to kill existing gametocytes, rather than simply preventing them from differentiating (see Figure 1.1).

1.3 Currently Available Antimalarials

The roots of most antimalarial treatments are based on three natural products: quinine, lapinone and artemisinin. In each case the natural product was known to have some activity from traditional medicine, and was isolated, shown to have some activity and then this activity was improved by classical medicinal chemistry.

The first widely used antimalarial drug was quinine, a natural product extracted from the bark of the tree Cinchona calisaya. It causes parasite death by blocking the polymerisation of the toxic by-product of haemoglobin degradation, haem, into insoluble and non-toxic pigment granules, resulting in cell lysis and parasite cell autodigestion. This means that the parasite is not able to generate resistance at the target site: the molecular target is a non- mutatable chemical reaction. Quinine itself is active when given 3 times a day for 7 days. Initial attempts to synthesise quinine led to the synthesis of dye substances, some of which are actually antimalarials in their own right, such as methylene blue. Later work produced chloroquine, a 4-aminoquinoline, which was the mainstay of malaria prophylaxis and treatment for the second half of the 20th century. This also has the advantage that its electronics allow it to selectively concentrate into the food vacuole. Further synthetic work has yielded many more aminoquinolines and related amino-alcohols such as amodiaquine, me?oquine, halofantrine, lumefantrine, piperaquine and pyronaridine. These medicines are characterised by a large volume of distribution and a long half life (terminal half lives of over 5 weeks are reported for choloroquine). They also require reasonably high doses (total dose of between 1250 and 2500 mg for adults, normally split into three daily doses. They have been linked to cardiac safety issues: at high doses prolongation of the QTc interval has been seen with some medicines, and indeed this led to the withdrawal of halofantrine by SmithKlineBeecham. Two more recent medicines in this class are Ferroquine (SSR97193, by sanofi-aventis, in phase II) and naphthoquine (launched as ARCO, by Kunming Pharmaceutical Coroporation). Both have long half lives, and the clinical question is whether their therapeutic window is large enough to support a single dose as a cure. Naphthoquine is administered as a 400 mg single dose with artemisinin and is reported to be safe and effective in small scale clinical trials, although the key data on QTc prolongation are currently not available. Ferroquine is currently in phase II trials with a lowest adult dose of 100 mg. An alternative approach has been to produce chloroquines linked to molecules known to reverse the CQ resistance transporter. Although this is synthetically interesting, the challenge is still to show superiority in cardiovascular safety, which is far from trivial. In addition, molecules such as azithromycin have been shown to reverse chloroquine resistance clinically, and so the challenge for a new molecule will always be to demonstrate additional benefit over known medicines.

Lapachol is a hydroxynaphthoquinone used to treat malaria and fevers in South America. It was initially reported in the 19th century. As part of the American war effort it was tested in P. lophurae infected ducks in 1943, and showed weak activity. A close synthetic derivative, lapinone, was also active. This was subsequently confirmed in patients with P. vivax by intravenous administration for 4 days. Solving the bioavailability issues led to the development of the orally bioavailable, metabolically stable molecule atovoquone, one of the active ingredients for Malarone, the current mainstay of antimalarial prophylaxis for travellers. Further work focussed on the 4-pyridones and led to the development of GSK932121. Work on this molecule was stopped in phase I after safety concerns with a pro-drug formulation. Hydroxynaphthoquinone and 4-pyridines target the cytochrome bc1 complex, and so in addition to the solubility/bioavailability and drug metabolism issues, there is clearly with such molecules a need to show selectivity against inhibition of the host electron transport. Recently, new inhibitors with selective bc1 inhibition have been reported based on an acridinone template WR 249685.

The third approach is built on the discovery of the sesquiterpene lactone artemisinin (known as Qing hao su) in 1972 by Chinese scientists. It is an endoperoxide-containing natural product isolated from the leaves of the sweet wormwood, Artemisia annua. Derivatives of artemisinin were subsequently shown to be more potent than the parent molecule, including dihydroartemisinin (DHA, believed to be the main active metabolite of all the derivatives), artemether, artemotil and artesunate (see Figure 1.2). Artemisinin itself is highly insoluble: chemical modification to artesunate increases oral bioavailability, and also makes it suitable for intravenous administration in severe malaria. The artemisinin derivatives are fully active against all existing drug-resistant strains of P. falciparum. Unlike all other antimalarial drugs, they act on all stages of the parasite intraerythrocytic life cycle and therefore rapidly kill all the blood stages of the parasite, resulting in the shortest fever and parasite clearance times of all such medicines. Furthermore, the artemisinins also kill gametocyte stages – thereby reducing transmission from humans to mosquitoes.

Not all antimalarial drugs can be traced back to natural products. Some were rationally designed following an antimetabolite approach. For example, malaria parasites are unable to salvage folate, but need this cofactor to synthesise tetrahydrofolate for methylation reactions. Inhibitors of dihydropteroate synthase (sulphonamides such as sulphadoxine) and dihydrofolate reductase (2,4-diaminopyrimidines such as pyrimethamine) are potent anti-malarial drugs, especially when administered in combination.

For most of the second half of the 20th century, control of acute uncomplicated malaria caused by all four species of Plasmodium relied on chloroquine for first-line treatment and a combination of sulphadoxine and pyrimethamine (SP) as second-line treatment.

1.4 Resistance

Resistance is a fact of life with antimalarial drugs, but the danger can be reduced by combination therapy. The frequency of mutations that might lead to resistance to drugs in P. falciparum is estimated at 1 in 1010 parasites compared with a parasite burden of 1012–1013 in humans with severe malaria. Combining two medicines with different mechanisms of action lowers the probability that a resistant parasite will emerge and become established. Against this background, it is not surprising that in all cases, Plasmodium strains resistant to current antimalarial drugs emerged. Resistance against drugs such as sulphadoxine-pyramethamine, where there are clear biological targets, arose more rapidly than with drugs such as chloroquine where the target is an immutaable chemical reaction and therefore other mechanisms, such as blockade of drug uptake, must be selected. Also, for reasons that are still not clear, resistance arose more rapidly in P. falciparum than in P. vivax. This might simply be an expression of less drug pressure, but this is by no means certain.

With the demise of chloroquine and SP because of drug resistance, in 2006 the WHO produced new treatment guidelines for uncomplicated P. falciparum malaria: they recommended that the treatment of choice should be a combination of two or more antimalarials with different mechanisms of action. More than this, they suggested that artemisinin monotherapy should be withdrawn, to protect the class against the emergence of resistance – the first time such a suggestion had been made. The standard treatment rapidly became artemisinin-based combination therapies (ACTs), moving towards fixed dose (with both drugs in the same tablet, to prevent the artesunate being used as monotherapy). Artemether-lumefantrine, the first such fixed-dose artemisinin combination therapy developed to international standards of good practice, was launched by Novartis in 2001. Amodiaquine-artesunate was developed as a fixed-dose combination by the Drugs for Neglected Diseases Initiative (DNDi), and launched in 2008. The same year, a paediatric-friendly version of artemether-lumefantrine was launched as the result of a collaboration between Novartis and Medicines for Malaria Venture. In 2010, 82 million people were treated with Coartem or Coartem-D artemether-lumefantrine, and an additional 21 million treatments of generic artemether-lumefantrine were sold, mainly subsidised by the Affordable Medicines for Malaria Facility AMFm. The second most important combination by volume was amodiaquine-artesunate produced mainly by sanofi-aventis, with around 45 million courses of treatment supplied in 2010. So far, three generic producers of artemether-lumefantrine have been set up in Africa, and are able to supply drugs at the same price as Novartis ($0.30 for the smallest children, through to $1.20 for adults). Two other fixed-dose combinations are due to be launched over the next year: DHA-piperaquine (a collaboration between Sigma-Tau and Medicines for Malaria Venture) and pyronaridine-artesunate (a collaboration between Shin Poong and Medicines for Malaria Venture). Another version of DHA-piperaquine is available from Holley-Cotec. A fixed-dose combination of mefloquine-artesunate is available in Brazil from Drugs for Neglected Diseases initiative/Farm-anguinhos/Fiocruz and in Europe from Mepha. A final combination of artemsinin (not the soluble artesunate) with naphthoquine has been marketed by Kunming Pharmaceutical Corporation: although this has the advantage on paper of being a treatment given in a single dose, or two doses in the same day, there are few data around the long-term safety, and no clinical studies have been carried out to determine good clinical practice. In summary, in 2010, over 150 million treatments for malaria were produced, enough for 60% of the cases of malaria identified globally. This is a tremendous step forwards compared with 5 years ago, when less than 10% of malaria patients were getting the best-quality treatments. (See Table 1.1).

(Continues...)

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Edition details

• Publisher: Royal Society of Chemistry
• Publication date: 2011
• ISBN 10: 1849731926
• ISBN 13: 9781849731928
• Binding: Hardcover
• Language: English
• Number of pages: 458
• Editor: Michael J Palmer