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It is the aim of this volume to explore the study of 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. Macrocyclic molecules, herein defined as molecules with rings of 12-members or larger, have figured prominently in the history of medicinal chemistry, with the most common source of these compounds being from natural products. In fact, numerous macrocycles have become important drugs or have been identified as leads to marketed drugs.

Of late, interest in macrocycles and their novel architectures has increased significantly as their potential for interacting with a variety of targets including kinases, ATPases, proteases, GPCRs and others has been recognized. Furthermore, as more non-classical drug targets, such as protein–protein interactions (PPIs), are pursued in the pharmaceutical industry, macrocyclic molecules have attracted significant attention since they offer the potential to provide drug–protein interactions that cover a larger surface area than traditional small molecules. This text will discuss the identification, optimization, pharmacology and synthesis of biologically active macrocyclic compounds in the context of their broad chemotype as compounds composed of large rings.

In the first chapter of this volume the wide variety of bioactive macrocyclic natural products is explored, including examples of those with clinically validated anti-infective and anti-tumor activity. Many of these natural products have been the subject of drug discovery efforts that have leveraged semi-synthesis, biosynthesis and total synthesis in order to investigate or optimize their pharmacological effects and viability as drugs. The medicinal chemistry of these macrocyclic natural products is interesting in itself, but lessons learned from these compounds, particularly in terms of the relationship between structure and desirable physicochemical properties, are now informing and driving the design of fully synthetic macrocyclic drug candidates.

Macrocyclic inhibitors of the chaperone protein Hsp90 are the subject of the second chapter. This ATPase is an important oncology target against which a variety of macrocyclic scaffolds have demonstrated activity, including the natural products geldanamycin and radicicol, and their derivatives, as well as fully synthetic, designed macrocyclic aminobenzamide derivatives, all of which bind to the N-terminal ATP binding domain. In this case structural information gathered on the binding of the natural products to Hsp90 was important for guiding the design of the fully synthetic macrocyclic inhibitors. Macrocyclic inhibitors of the Hsp90 N-middle domain related to the penta-depsipeptide sansalvamide A are also known and discussed in this section.

The third chapter of the volume describes the in vitro and in vivo activity of the natural occurring microtubule stabilizer epothilone B and its analogs. This macrocyclic natural product has been the subject of extensive medicinal chemistry research and numerous derivatives have been studied pre-clinically and clinically for oncology indications. One such compound, ixabepilone (BMS-247550; Ixempra®) was approved by the FDA in 2007 for the treatment of breast cancer.

Chapters 4 and 5 are also focused on macrocycles with potential utility as anti-cancer therapeutics. Thus, Chapter 4 describes drug discovery efforts directed at the identification of inhibitors of a family of zinc-dependent enzymes known as histone deacetylases (HDACs). Interestingly, a variety of macrocyclic natural product HDAC inhibitors are known, including cyclic peptides and depsipeptides with a diverse set of zinc-binding warheads, as well as fully synthetic inhibitors. This epigenetic target has afforded two FDA approved inhibitors as oncology therapeutics, one an acyclic hydroxamic acid derivative and the second a macrocyclic disulfide natural product, FK228, that undergoes reductive ring cleavage to reveal the active species bearing a thiol zinc chelator.

The search for macrocyclic kinase inhibitors is detailed in Chapter 5, starting from macrocyclic bisindolylmaleimide analogs of staurosporine, the initial foray into this area thirty years ago by chemists at Lilly in search of novel protein kinase C inhibitors, to more recent drug discovery efforts into potent inhibitors of CDKs, JAK2 and FLT3, among other kinases, driven by structure-based design. The rational design of macrocyclic kinase inhibitors with desirable, indication-specific, kinase selectivity profiles and oral bioavailability has been particularly exciting and has yielded several molecules now in clinical trials for the treatment of cancer and rheumatoid arthritis.

The sixth chapter of this volume explores the use of macrolides, macrocyclic lactone polyketide natural products best known for their antibacterial activity, for their anti-inflammatory activity. The propensity for these molecules, exemplified by azithromycin, to accumulate in inflamed tissue and polarize macrophages is discussed in detail. In addition, a creative and exciting drug discovery approach has been taken that investigates the ability of macrolides to act as carriers of small molecule payloads in order to transport them into immune cells. Thus, small molecule inhibitors with diverse biochemical targets including p38 kinase and lipoxygenase, as well as steroidal and non-steroidal anti-inflammatories, have been conjugated to macrolides and have demonstrated activity in in vitro assays and in vivo animal models of inflammatory disease and cancer.

The identification and optimization of macrocyclic molecules that inhibit a broad array of target classes such as proteases, G protein-coupled receptors (GPCRs), integrins and PPIs, is thoroughly reviewed in Chapters 7, 8 and 9. Chapter 7 focuses on providing background on the hugely important and competitive area of research surrounding the discovery and development of macrocyclic HCV protease inhibitors with multiple agents in clinical trials and progressing to the market. The concept of macrocyclization as applied to HCV protease inhibitors was driven by the seminal work from researchers at Boehringer-Ingelheim, and its translation into the optimization of boron-containing irreversible inhibitors of this enzyme is presented. This is followed by an extensive review in Chapter 8 of macrocycles that target GPCRs, both agonists and antagonists, integrin inhibitors and the rapidly expanding field of macrocyclic modulators of protein-protein interactions. That theme is further extended in Chapter 9 with a discussion of stapled peptides. These fascinating macrocyclic molecules are constructed to lock peptidic ligand molecules in an α-helical conformation, most often through the use of a hydrocarbon linker, for recognition by their targets. An extraordinary effort combining computational chemistry, structural biology, chemical biology and organic synthesis has enabled the evolution of this chemotype into one that can deliver stapled peptides with sufficient cell penetration and in vivo exposure to advance into the clinic, as is the case for the MDM2/MDMX antagonist ALRN-6924, being studied for the treatment of p53-dependent cancers.

This volume concludes with two chapters that describe efforts that will truly enable the expansion of the field of macrocyclic molecules for drug discovery and the treatment of disease. Chapter 10 covers ongoing efforts to understand the factors that affect the permeability and bioavailability of macrocyclic compounds and comes full circle with some of the natural products described in Chapter 1. Thus, the field of medicinal chemistry has, over the last 15 years in particular, focused on deciphering the relationship between the physical properties of a molecule and its oral bioavailability, since there is a great preference for small molecule drugs to have the convenience of oral dosing. With this in mind, the natural products that do not adhere to standard Rule of Five guidelines yet do display reasonable oral bioavailability have become the subject of intense scrutiny in an attempt to understand how and why they are able to be orally absorbed so that those principles can be applied to additional molecules outside of the Rule of Five space.

Finally, Chapter 11 provides the last piece in the puzzle for delivering macrocyclic molecules for drug discovery programs and advancing them into clinical trials and ultimately to the market for the benefit of patients. Therefore, in order to optimize macrocycles for potency against a target and pharmacokinetics, to make sufficient quantities to test in animal models of efficacy and toxicity, and to manufacture these materials on large scale for commercial use, one needs to be able to devise and execute practical, scalable routes for their synthesis. Chapter 11 provides an exhaustive survey of the methodologies that have been used to generate these molecules.

In summary, this volume covers a selection of the most active and promising areas of research ongoing in the discovery of macrocycles for therapeutic use and we hope it provides valuable insight into the challenges encountered and solved for this diverse class of molecules.

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