Macrocycles in Drug Discovery: Volume 40 (Drug Discovery Series) - Hardcover

Hardcover

ISBN 10: 1849737010 ISBN 13: 9781849737012

Publisher: Royal Society of Chemistry, 2014

Synopsis

This series provides a comprehensive resource for postgraduate students and for scientists in academia or industry wanting to learn topics outside their own areas of expertise.

About this title

About the Author

Jeremy Levin is currently a Director of Medicinal Chemistry at Boehringer Ingelheim Pharmaceuticals, with a total of 25 years of experience in the pharmaceutical industry. He has worked in multiple therapeutic areas, including CNS, inflammation and immunology, and oncology. Dr Levin has authored or co-authored more than 70 papers in peer reviewed journals and served as an inventor on more than 60 issued U.S patents.

From the Back Cover

This book reviews macrocycles in drug discovery, both those of natural origin and semi-synthetic derivatives of natural products, and those designed and synthesized based on principles of medicinal chemistry.
The medicinal chemistry of macrocyclic natural products is interesting in itself, but lessons learned from these compounds, in terms of the relationship between structure and desirable physicochemical properties, are now informing the design of fully synthetic macrocyclic drug candidates against a variety of targets including kinases, ATPases, proteases, GPCRs and others. Furthermore, as more non-classical drug targets, such as protein-protein interactions, are pursued in the pharmaceutical industry, macrocyclic molecules are generating increasing interest as they offer a way to provide drug-protein interactions that cover a larger surface area than traditional small molecules.
A variety of macrocycles have become important drugs or have been identified as leads to marketed drugs. This text will discuss these compounds, their pharmacology and synthesis, in the context of their broad chemotype as compounds composed of large rings. Providing a wide reaching review of this important area in a single volume, this book will be of interest to biochemists, pharmaceutical scientists and medicinal chemists working in industry or academia.

Excerpt. © Reprinted by permission. All rights reserved.

Macrocycles in Drug Discovery

By Jeremy I. Levin

The Royal Society of Chemistry

Copyright © 2015 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-84973-701-2

Contents

Macrocycles in Drug Discovery: Introduction, xxi, 
Chapter 1 Bioactive Macrocycles from Nature David J. Newman and Gordon M. Cragg, 1, 
Chapter 2 Recent Advances in Macrocyclic Hsp90 Inhibitors D. M. Ramsey, R. R. A. Kitson, J. I. Levin, C. J. Moody and S. R. MCAlpine, 37, 
Chapter 3 Epothilones Raphael Schiess and Karl-Heinz Altmann, 78, 
Chapter 4 Macrocyclic Inhibitors of Zinc-dependent Histone Deacetylases (HDACs) A. Ganesan, 109, 
Chapter 5 Designed Macrocyclic Kinase Inhibitors Anders Poulsen, Anthony D. William and Brian W. Dymock, 141, 
Chapter 6 Anti-Inflammatory Macrolides to Manage Chronic Neutrophilic Inflammation Michael Burnet, Jan-Hinrich Guse, Hans-Jürgen Gutke, Loic Guillot, Stefan Laufer, Ulrike Hahn, Michael P. Seed, Enriqueta Vallejo, Mary Eggers, Doug McKenzie, Wolfgang Albrecht and Michael J. Parnham, 206, 
Chapter 9 Macrocyclic a-Helical Peptide Drug Discovery Tomi K. Sawyer, Vincent Guerlavais, Krzysztof Darlak and Eric Feyfant, 339, 
Chapter 10 Optimizing the Permeability and Oral Bioavailability of Macrocycles Alan M. Mathiowetz, Siegfried S. F. Leung and Matthew P. Jacobson, 367, 
Chapter 11 The Synthesis of Macrocycles for Drug Discovery Mark L. Peterson, 398, 
Subject Index, 487, 

CHAPTER 1

Bioactive Macrocycles from Nature

DAVID J. NEWMAN AND GORDON M. CRAGG

1.1 Introduction

Natural products have been an important source of pharmacologically active molecules throughout the history of medicinal chemistry and a selection of these molecules has advanced to provide clinically validated, marketed therapeutics for numerous indications, most notably as antibiotics, immunosuppressives and anti-tumor agents. Among these, structurally diverse and complex naturally derived macrocycles have demonstrated an impressive record of efficacy as pharmaceutical agents, and are playing an increasingly important role in the treatment of a range of serious diseases. These macrocycles have received intense recent interest from the medicinal chemistry community driven in part by their activity in biological systems, such as those mediated by protein–protein interactions, that are difficult to prosecute with more typically drug-like small molecules. In addition, the selectivity afforded by their complexity and the remarkable ability of some of these macrocyclic natural products to provide significant systemic exposures on oral dosing despite physical properties that lie substantially outside of normal parameters for achieving oral bioavailability, make them an attractive chemical class. Thus, these macrocyclic natural products and related biosynthetically and semi-synthetically derived macrocycles are of great value not only for their own intrinsic pharmacological activity but also or their potential as tools used to understand how to design molecules with he properties necessary to produce highly effective therapeutics for the treatment of human disease.

Further testaments to the current level of focus on macrocycles in drug discovery are the excellent reviews published over the last five years on key aspects of the medicinal chemistry of this chemotype. The most recent of these reviews, by Giordanetto and Kihlberg, provides an analysis of the physical properties of macrocyclic drug molecules, including cLogP, polar surface area, hydrogen bond donor count and molecular weight, in relationship to their ability to be orally efficacious. In addition, in 2008, Driggers et al. provided an excellent overview of macrocycles as drug leads and candidates at that time. This was followed by a review in 2011 by Marsault and Peterson showing the use of macrocycles over a wide area of medicinal chemistry and, in 2012, a review from Mallinson and Collins focusing primarily on potential anticancer agents.

In their 2014 review Giordanetto and Kihlberg reported 68 registered macrocyclic drugs approved for human use (identified through mining of the GVK BIO online structure-activity relationship database (GOSTAR)), along with a set of 35 macrocyclic drug candidates in clinical development (identified using the Adis R&D Insight database). The latter set did not include compounds in early clinical trials whose structures were not in the public domain. Most of these drugs, which have macrocyclic rings comprised of 12 or more atoms, fall into three chemical classes, namely macrolidic antibiotics, macrolides that have antitumor or immunological effects, and cyclic peptides that may or may not contain lactone (depsipeptide) linkages.

Of the 68 identified macrocyclic registered drugs, 34 are used for the treatment of infections, mainly of bacterial origin, while 10 are used for the treatment of a variety of cancers; the remaining 28 are applied in cardio-vascular, gynecological and immunological therapeutic areas, as well as in a range of indications, including anesthesiology and pain (these numbers do not total 68 since some agents have two or more activities). The majority of these molecules are natural products or directly derived from natural products (48 and 18, respectively), while eribulin (vide infra) is totally synthetic but modeled on the marine natural product, halichondrin B, and Sugammadex is a modified γ-cyclodextrin. Nineteen of the 68 drugs are administered orally, with 15 of these belonging to the macrolide classes. The parenterally administered macrocyclic drugs include all of the cyclic peptides, with the exception of cyclosporin A which is orally delivered.

As with the registered drugs briefly discussed above, of the 35 macrocycles identified as agents in clinical development 14 are under investigation for the treatment of various cancers, 10 are in infectious disease trials, and the remaining 11 are under investigation for indications ranging from endocrinology to ophthalmology. While these agents are also predominantly natural products (17) or natural product-derived molecules (8), with the largest chemical class being cyclic peptides (11), 10 of the clinical candidates are of de novo design. A total of 43% of these clinical candidates are administered orally, a significant increase over the 28% of all registered macrocyclic drugs that are orally administered, and nine of the 10 de novo designed macrocycles in trials are orally bioavailable. The increasing numbers of orally active macrocyclic drug candidates indicates that organic and medicinal chemists are learning to apply the lessons provided by bioactive natural macrocyclic agents, such as those presented in this chapter, for the design of fully synthetic molecules having desirable pharmacological properties, including oral bioavailability.

In strongly endorsing the impressive therapeutic record of natural product-derived macrocycles reported in earlier reviews and commentaries, the following sections will expand on the discussion of the macrocyclic chemical classes mentioned above, while adding a number of other chemical compounds that fall under the general description of "macrocycles" that have originated from plant and marine sources. Some of these compounds have arisen from the assessment of biosynthetic clusters that has led to the identification of novel agents, frequently not associated with the "expected" macro-organism source.

Also included are two short sections covering natural product macro- cycles, which are described in detail in two later chapters of this volume. In the case of the ansamycin Hsp90 inhibitors, some of the very early work has been referenced, as the authors of this chapter were involved in the initial production of geldanamycin for the NCI's work with 17-AAG and 17-DMAG. This is followed by some current examples, where the manipulation of biosynthetic clusters in the producing bacteria has led to ansamycin structures that are completely novel and Hsp90 active. Similarly, with the epothilones, which are covered extensively in Chapter 3, particularly from a synthetic chemistry aspect, it is shown how genetic manipulation of the base-producing cluster and expressing it in heterologous hosts permitted the production of quantities of the four basic epothilones, and also materially aided in the utilization of myxobacteria as sources of novel agents, mainly via genomic techniques.

1.2 Macrolides and Peptide-based Bioactive Compounds

1.2.1 Non-Ansamycin Antibiotics (Anti-infective and Anti-tumor)

1.2.1.1 Actinomycins

It can be successfully argued that the discovery of the actinomycins by Waksman and Woodruff in 19405 led to at least two firsts: the first crystalline antibiotic and the first demonstration of anti-tumor activity (actinomycin C) in vitro. This was followed by a report later in 1952 by Schulte demonstrating the first clinical studies with these agents. Over the last 60 plus years, actinomycins, usually as actinomycin D (Figure 1.1, 1), have been used as treatments for a variety of tumor types. Currently actinomycin D is used primarily for the treatment of rhabdomyosarcoma and Wilms' tumor in children and young adults, with a very recent example being its reported use in the treatment of a patient with uterine embryonal rhabdomyosarcoma, 50 years after its formal launch in 1963.

Two major mechanisms of action, involving intercalation of DNA and stabilization of cleavable complexes of topoisomerases I and II with DNA, have been discussed in a review by Mauger and Lackner. In 2003, Gniazdowski et al. reported that actinomycin D interacted with downstream proteins associated with transcription, and this activity appeared related to its DNA-intercalating ability, but at levels well below those demonstrating anti-tumor activity. In contrast, in a recent review, Leung et al. did not confirm this earlier report but did show that another complex depsipetide, echinomycin demonstrated such activity at the transcription factor level (vide infra). Studies reported in 2009 by Kang and Park showed that actinomycin D binds to oncogenic promoter G-quadruplex DNA repressing gene expression. Formally, actinomycins can be considered as two separate depsipeptides (the macrocycles) linked viaa phenoxazine nucleus with differing amino acids in the depsipeptides, depending upon the actinomycin variant in question. For a much fuller description of the history of actino-mycins, the significant chemical synthetic and semi-synthetic programs since its introduction and their activities, the 2012 review by Mauger and Lackner should be consulted.

1.2.1.2 Erythromycin and Related Macrolides

Although not the first antibiotic to go into general clinical use, erythromycin (Figure 1.1, 2), which was introduced in 1952, was certainly the first of the bioactive macrolidic agents to become an anti-infective drug. Even today, 60 years later, variations, usually with a change in the salt form, are still in clinical trials, and the parent molecule has been almost a "poster child" for what could be done to follow the biosynthesis, initially by using radio-labeled production of the base aglycone, the macrolide erythronolide B and then the work over many years by Abbott scientists and their successors in the production of variations of the base macrolide. These derivatives were prepared by biosynthetic manipulations as recombinant DNA technologies advanced, coupled to fundamental knowledge of how to manipulate gene clusters in antibiotic producing microbes. A large amount of the work using these techniques was performed by the now defunct Kosan, Inc., and modifications of the base structure using biosynthetic techniques to produce what might best be called, un-natural natural products are still being published, with the alkynyl substituted erythromycin (Figure 1.1, 3) being an excellent example.

Over the last 25 years, in addition to this type of biosynthetic process which has not yet led to an approved agent, a number of macrolide antibiotics have been launched based upon the erythromycin core structure. In each case, the compounds were optimized to overcome problems with the parent molecule from an antibiotic perspective. These approved agents included the first azalide azithromycin (Figure 1.1, 4) launched in 1988, a long-acting agent that is now generic in the USA. Other approved drugs with the base erythronolide structure include midecamycin (Figure 1.1, 5) launched in 1985, rokitamycin (Figure 1.1, 6) in 1986, roxithromycin (Figure 1.1, 7) in 1987, clarithromycin (Figure 1.1, 8) in 1990, flurithromycin (Figure 1.2, 9) in 1997, dirithromycin (Figure 1.2, 10) in 1993, telithromycin, the first ketolide, (Figure 1.2, 11) in 2001, and fidaxomycin (Figure 1.2, 12) in 2011. In addition to these, solithromycin (Figure 1.2, 13) is now in Phase III clinical trials for the treatment of Community-acquired Bacterial Pneumonia (CaBP).

1.2.1.3 Synergistic Antibiotic Mixtures

In the 1960s and later, synergistic antibiotics that were mixtures of two macrolides, known collectively as streptogramins, were in use as agents to alter food uptake and metabolism, predominantly in ruminants. Following the advent of Gram positive resistant organisms, in particular methicillin resistant Staphylococcus aureus (MRSA), and the lack of suitable treatments for these and other more resistant Gram positive microbes in humans, these old compounds were used as templates for chemical modification, leading to the approval and subsequent launch in 1999 of the quinuprisitin (Figure 1.3, 14)/dalfoprisitin (Figure 1.3,15) 1 : 1 mole ratio defined mixture under the name Synercids in the USA. At this moment, another similar mixture of related compounds is in Phase II clinical trials with Novexel, using linopristine (Figure 1.3, 16) and flopristine (Figure 1.3, 17) as the components of the mixture.

1.3 Ansamycins (Antimycobacterial and Antibacterial)

1.3.1 Rifamycins

The base structure of the rifamycin class of macrocyclic antibiotics can be best thought of as a single or fused ring (usually two) linked within a larger macrolidic ring (Figure 1.3, 18). The base molecule in this series was launched in the middle 1960s as an antimycobacterial (tuberculosis) agent, and in the intervening five decades, well over 300 variations on the structure have been reported as being in biological assessments ranging from in vitro testing, through clinical trials, to becoming approved drugs. A search of the Thomson–Reuters Integrityt database in December 2013 showed 177 different compounds listed of similar structure, with 7 being shown as launched.

A relatively recent paper by Mariani and Maffioli gives an excellent comparison of the various rifamycins and also leads into discussions of other ansamycin molecules including the geldanamycins and ansamitocins, both of which will be mentioned later.

In addition to rifamycin, four other variations have been marketed since that approval: rifampicin in 1967 (Figure 1.3, 19), rifamixin in 1988 (Figure 1.3, 20), rifabutin (Figure 1.3, 21) in 1992 and rifapentine (Figure 1.3, 22) in 1998. As of December, 2013, there appear to be no rifamycin-like molecules in clinical trials for mycobacterial infections, though a recent publication in the infectious disease literature does imply that increased doses of these agents in conjunction with other anti-tuberculosis drugs are still viable treatments.

Of additional interest is the report in August 2012, that three rifamycins, rifampicin, rifamixin and rifabutin, have been found to be effective in preventing the growth and cellular respiration of multidrug resistant (MDR) Acinetobacter baumanii (MDRAb), which is an important pathogen associated with wound infections afflicting US military personnel.

1.3.2 Anthracimycin

Although not an erythromycin-based molecule, nor an ansamycin of the normal basic structure for these agents due to the linkages of the macrolide ring, a very recent paper from the Fenical group at the Scripps Institute of Oceanography reported the isolation and identification of the 14-ring macrolide known as anthracimycin (Figure 1.4, 23) from a streptomycete isolated from marine sediments. The name chosen was due to its activity against both Bacillus anthracis and methicillin-resistant Staphylococcus aureus and according to the authors only one other structure similar to this has been reported to date and that was from a myxobacterium in 2008. Thus, even today novel bioactive macrocyclic agents are still being found.

1.3.3 Ansamitocins (Tubulin Interactive Agents)

Very recently, one of the first "plant-derived" tubulin interactive compounds that can be considered a bioactive macrocycle to enter clinical trials, may-tansine from the Ethiopian tree Maytenus serrata, was effectively granted a new lease of life as a slightly modified "warhead" that could be conjugated to a monoclonal antibody to provide potent and selective anti-tumor agents.

From the initial determination of its structure (Figure 1.4, 24) natural product chemists wondered if the compound was microbial in origin, due to its similarity to the "ansa" antibiotics such as the rifamycins. In 1977, scientists at Takeda Chemical Industries reported the structures of the bacterial products, the ansamitocins, which very closely resembled the maytansenoids. Later work on compounds isolated from the bacterium, subsequently renamed as Actinosynnema pretiosum, demonstrated that they were in fact identical to those isolated from other plant genera. The work leading up to this determination has been well covered in a review by Kirchning et al. in 2008 and/or the chapter by Yu et al. in 2012, as these cover the chemistry and biosynthesis of these microbial compounds.

(Continues...)

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Edition details

• Publisher: Royal Society of Chemistry
• Publication date: 2014
• Language: English
• ISBN 10: 1849737010
• ISBN 13: 9781849737012
• Binding: Hardcover
• Number of pages: 468
• Editor: Jeremy Levin