By S. Kafa. Bloomfield College.
This in turn has inspired the development of several truly innovative thera- peutic strategies aimed at correcting the underlying pathology generic 75 mg lyrica amex. Acknowledgements The authors wish to thank Professor Dame Kay Davies cheap lyrica 75mg mastercard, Professor Steve Davies and Dr Robert Westwood for helpful advice and comments buy cheap lyrica 150 mg line, and for proof- reading this manuscript buy cheap lyrica 75 mg on line. Databases: Chemical Abstracts and PubMed; searched using the search terms ‘Duchenne Muscular Dystrophy’ and ‘Spinal Muscular Atrophy’ respectively. Bivona, Duchenne Muscular Dystrophy Drug could Unlock Huge Potential for this Pharmaceutical, http://beta. Tatem, View Online Drug Discovery Approaches for Rare Neuromuscular Diseases 329 K. Summit Outlines Clinical Development Plans For Utrophin Modulator Programme For Duchenne Muscular Dystrophy, http://www. Dansette, in The Practice of Medicinal Chemistry, 3rd edition Academic Press, 2008, pp. Summit Outlines Clinical Development Plans for Utrophin Modulator Programme for Duchenne Muscular Dystrophy, http://www. Janssen, Identication of Compounds Enhancing Utrophin Expression in Primary Human Skeletal Muscle Cells, http://www. Pzer Licenses Families of Spinal Muscular Atrophy Quinazoline Drug Program from Repligen, http://www. Improved precision in isolation, purication, char- acterisation and production have increased the availability of these secondary metabolites to explore their inherent chemical and biological diversity. Enriched with complex, multifunctional and distinct molecular landscapes, natural products provide creative starting points for medicinal chemists to test hypotheses via semi-synthetic manipulation. There are signicant challenges to this research: availability of the natural product in suﬃcient quantity with suitable purity, chemical stability of the molecule, limitations of available and requisite transformations, analyses and purication methods, and notably precise structure–activity requirements. Achievement of semi- synthetic goals mandate accountability for the above-mentioned synthetic limitations coupled with synthetic eﬃciency aﬀorded by judicious design of synthetic pathways. Thus, successful strategies further result in the devel- opment of new synthetic methods and reagents, optimisation of reaction conditions, and creation of enabling analytical and purication technologies (Figure 12. View Online Unleashing the Power of Semi-Synthesis: The Discovery of Torisel ® 349 Figure 12. To date, ingenious and divergent solutions to this daunting problem have been achieved evinced by the ve total syntheses that have been reported. One goal was the identication of development candidates for trans- plantation and for other therapeutic indications. In this regard, the team needed to be cognisant of pharmacological parameters (potency, eﬃcacy, metabolism, bioavailability), physical properties (stability, solubility, crys- tallinity, solid form) and synthetic processes (reactivity, selectivity, stability, reagents, purication). Primary in vivo models were the mouse skin gra rejection model and the rat adjuvant arthritis model. In addition, numerous mech- anistic assays and models were developed to enable advanced pharmaco- logical assessment. With its intricate juxtaposition of functional groups, rapamycin provides a fertile and versatile platform for semi-synthesis. Modication of rapamycin is challenging but rewarding, and must take into account a 31-membered ring containing both a lactone and a lactam, an all-trans triene unit, 15 chiral centres, a masked contiguous tricarbonyl region, an allylic alcohol, a b,g-unsaturated ketone, and a segment susceptible to b-elimination (Figure 12. Rapamycin derivatives may serve as biochemical tool molecules or potential drug candidates and semi-synthetic manipulations are designed to anticipate substitution patterns or conformational changes that aﬀect binding to either of the two protein partners. As part of a programme aimed at the identication of novel rapamycin analogues, we have explored systematic semi-synthetic point modications to functional groups at essential regions of the molecule. These include, amongst others, alcohol functionalisation, alteration of the triene unit, manipulation of the carbonyl groups, modication of the pipecolinate region, ring opening, contraction and expansion (Figure 12. Each compound was designed to probe specic properties and to expand knowl- edge in the rapamycin arena. Using these semi-synthetic derivatives, the Wyeth team introduced and developed creative strategies to perturb and distinguish fundamental biological processes, probe pharmacological attri- butes, elucidate chemical characteristics and optimise pharmaceutical properties. To this end, the scope of synthetic transformations was dened, View Online Unleashing the Power of Semi-Synthesis: The Discovery of Torisel ® 351 Figure 12. Through this process, Wyeth had identied and developed considerable equity in rapamycin analogues initially targeted for use in transplantation/ immunoinammatory programmes. Numerous semi-synthetic derivatives displayed potent in vitro activity and in vivo eﬃcacy. Both compounds exhibit potent activity against a histologically diverse panel of cell lines and displayed anti-tumour activity against a panel of human xenogras in nude mice. In this chapter, the medicinal chemistry target design rationale and strategy for rapamycin analogues will be highlighted, exploring the afore- mentioned systematic point modication approach. The scope and limita- tions of synthetic transformations will be illustrated; synthetic challenges and their solutions will be described. Details of the preclinical pharmacology studies of temsirolimus have been reported and will not be discussed further. To focus the article, not all compounds and experiments are exemplied, but an ensemble of diverse and essential chemical approaches are delineated. In this region, the initial, sustained and primary focus of these synthetic eﬀorts was the derivatisation of the C-42 alcohol. The C-42 position is synthetically acces- sible, providing a fertile derivatisation platform and the alcohol functionality View Online Unleashing the Power of Semi-Synthesis: The Discovery of Torisel ® 353 provides an important handle for a variety of synthetic manipulations. From our experience, we have observed that the C-42 position could accommodate chemistry to yield functional groups of various size, shape and constitution; these include, but are not limited to, preparation of ethers, acetals, ketones, carbonates, epimerised alcohols and ethers, sulfonates, esters and carba- mates. In cases where a mixture of C-42, C-42/C-31 and C-31 products are formed in the reaction, these are separated chromatographically. The C-42 esters of rapamycin have been prepared by four diﬀerent methods (Scheme 12. Acylation of rapamycin using acid chlorides, acid anhydrides, acids (carbodiimide coupling conditions), or by the Yamaguchi14 procedure, aﬀorded the candidate compounds. Carbamates were prepared by direct acylation of rapamycin using appropriately substituted isocyanates or in a two-step procedure involving sequential preparation (and isolation) of the nitrophenylcarbonate, followed by reaction of appropriately substituted amines. In this manner, the complexion of the acyl group with respect to functionality, size, steric considerations or polarity was varied. View Online 354 Chapter 12 and in ion spray mass spectrometry experiments to examine and analyse the energetics of gas-phase analogue–protein complexes. Representative triene modications have been designed to probe the boundaries of the eﬀector region (Figure 12. Catalytic hydrogenation of the triene has provided partial (both mono and di) or full reduction products, by alteration of reagents and reaction conditions. In a limited assessment, biological activity tracked with the extent of hydrogenation (C-1–C-7: rapamycin > diene > alkene > alkane). The authors postulate the intermediacy of a stabilised carbocation at C-7 via attack at the C-7 methoxy group. Another signicant alteration in this region involved the generation of a Diels–Alder adduct. Furthermore, this adduct antagonises the eﬀects of rapamycin on thymocyte proliferation. View Online Unleashing the Power of Semi-Synthesis: The Discovery of Torisel ® 355 Figure 12. To enhance the metabolic stability of rapamycin while retaining biological activity, the Wyeth group investigated manipulation of the C-27 ketone (Figure 12. A series of oximes23 (as mixture of syn and anti) and hydra- zones24 have been designed to alter the electronic and steric environments at this position. In another approach, regio- and stereospecic reduction of the ketone was eﬀected by protection of the C-42 and C-31 alcohols as triethylsilyl ethers, reaction with L-selectride, and deprotection. Good to excellent regiocontrol was observed with proper choice of reagents and conditions. Regioselective oxidation at C-31 was achieved using Dess–Martin period- inane (no C-42 ketone) was obtained bar small amounts of bis-oxidation (C-31, C-42). Reaction of the C-31, C-33 dicarbonyl system with hydrazine furnished the corresponding pyrazole as a mixture of tautomers. The authors hypothesised that alkylation at this position provides rigidity with resultant restricted rotation of the amide bond. Interestingly, reduction of the C-27 ketone (L-selectride) of the C-22 methyl congener provided an alcohol with View Online Unleashing the Power of Semi-Synthesis: The Discovery of Torisel ® 357 Scheme 12. A variety of esters and amides, reminiscent of the cyclohexyl region, were prepared by condensation with the liberated acid of the pipecolinate. Nonetheless, an ulterior motive for these eﬀorts was to serve as a model system for a tandem conjugate addition-acid functionalisation strategy to yield ring expanded rapamycin analogues.
Physical stability After 2 weeks at 40 °C no changes of aspect or viscosity were observed generic 150mg lyrica overnight delivery. After the am poules have been heat-sterilized buy lyrica 75 mg mastercard, they should be shaken for a short tim e purchase 75mg lyrica free shipping, while they are still hot discount 150mg lyrica, to elim inate any separation of the phases that m ay have occurred. Properties of the solution A clear colourless solution of low viscosity was obtained. Stored at 20 – 25°C in the day light the heat sterilized solution did not show any change of the clarity and colour after 12 weeks. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc. 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Library of Congress Cataloging-in-Publication Data: Peptide Chemistry and Drug Design / edited by Ben M. Summary: “This book details many of the problems and successes of peptides as potential drugs”– Provided by publisher. One additional infuence was a meeting in Dubai, where I had an excellent dinner with Waleed Danho, then with Roche Nutley. Waleed had given an excellent talk about the value of peptide chemistry and peptides as elements in the drug-discovery process. Over a delicious dinner of baked fsh and many other courses, we discussed the history of drug discovery and the role that peptides have played in the past. Waleed made the strong point that peptides still have great value in the discovery process and, with appropriate methods to deal with delivery and metabolism issues, can provide excellent drugs for the future. At around this time, I was contacted by Jonathan Rose of John Wiley & Sons who asked if I would be interested in editing a book on peptides and drug discovery. Sometimes life provides a nice juxtaposition of ideas and I immediately accepted the invitation. Over the following years, I spoke with many scientists, emailed some more, and worked on putting together the chapters for this book. I want to thank Jonathan as well as Kari Capone of John Wiley for their patience and advice over the years it took to bring this together. The book starts with a chapter provided by Nader Fatouhi, discussing the current state of peptides in drug discovery. I heard Nader speak at the 23rd American Peptide Symposium in the Kona region of the Big Island of Hawaii. As I felt that his pre- sentation provided an update on the thoughts frst revealed to me by Waleed Danho, I asked Nader to contribute the opening chapter of the book, as this sets the stage for what follows. Tools and techniques are available to address each of these limitations at this time. Included are sections on solid supports for solid-phase peptide synthesis, which dominates most research level approaches, linkers, protecting groups, methods for peptide-bond formation, and a variety of methods to modify peptides to limit metabolism. In all cases the latest reagents and techniques are featured, thus making this chapter a great starting point for scientists starting out in the peptide feld. The authors go on to discuss synthesis of peptides in solution, which still has great value in certain applications, includ- ing production of peptides in bulk. In addition, the combination of both solution- and solid-phase methods is discussed for cases where fragment condensation is used to prepare ever larger peptides. This discussion includes native chemical ligation, which permits selectively linking N-termini and C-termini of fragments, and which has several variations with more coming each year. The chapter concludes with a very valuable discussion of separation methods and methods for the analysis of the products of peptide synthesis. Anamika Singh and Carrie Haskell-Luevano have provided Chapter 3 that dis- cusses the important topic of membrane receptors as targets for drug discovery. This chapter provides a catalog of systems where peptides are known to be involved and where it has been shown that synthetic peptides can modulate function. The Haskell-Luevano lab has provided outstanding research on the melanocortin receptors, but this chapter takes a broader approach and discusses a wide variety of these systems, including structural information as known and as modeled by other labs. Anyone involved in aspects of membrane signaling will fnd this chapter a highly valuable resource for methods, approaches, and strategies for attacking this important area of biology. Gregg Fields and colleagues present Chapter 4 to introduce the use of peptides as inhibitors of enzymes. In the frst part, the authors introduce enzymes and their classifcation and present several classical examples of the use of peptides to come up with compounds that provide the desired change in enzyme function to overcome a metabolic defect. The Fields lab has made major contributions to discoveries in the area of matrix metalloproteinases and this chapter presents a thorough discussion of this system. The chapter continues with nice discussions of several other systems where peptide chemistry has been key in new discoveries that have driven the drug-development process. Jeffrey-Tri Nguyen and Yoshiaki Kiso have provided Chapter 5, which continues the discussion of enzyme inhibitors from the aspect of peptides. The highly productive Kiso lab has led the way in creating a very large catalog of peptide derivatives for use in drug discovery in several systems. They begin this chapter by discussing the advantages and disadvantages of peptides as potential drugs and come down on the side of the benefcial role that peptides play. In particular, they make the important point that the use of peptides can frequently defne the pharmacophore, or structural model, which can then be transformed into a small molecule of non-peptide nature for further development as a potential drug. This chapter further focuses on the process of the design of potential inhibitors and reviews the history of discovery from natural sources as well as through ab initio design. They discuss the advantages of learning from the natural substrates of an enzyme and introduce the important concept of the transition state analog; the critical role that structural information on the target protein can provide. This chapter provides an excellent discussion of systems where targeting with peptide molecules may provide opportunities for further drug discovery. The introduction to their chapter discusses the value of fnding compounds from nature and describes a number of sources, including the antimicrobial peptides from many bacteria. In both bacterial and plant worlds, there is a continual war between competing systems, and this has led to the development through evolution of many natural peptides that serve as defensive molecules. The authors discuss the cyclotides, peptides that are connected end to end and that have multiple disulfde bonds. This arrangement is very stable and the molecules are found in venoms of several species as well as in plants. After this introduction, the authors turn to a discussion of the drug discovery process from their perspective. The chapter continues with an in depth discussion of a variety of systems where many methods are used to modify molecules isolated from nature and where the activity against many targets is tested. The wide diversity of structures and targets is featured in this chapter and the many discoveries have pushed research and drug discovery forward signifcantly. Hruby have taken on the task of describing methods to limit the metabolism of peptide molecules in humans. As Victor Hruby is the world leader in this aspect of peptides, the chapter is thoroughly exciting and interesting. A main concern is the digestion of peptides by proteolytic enzymes present in both the digestive tract and the circulation. The frst step is to defne the pharmacophore residues of a naturally occurring and effective peptide. This will show the absolutely critical functional groups and their stereochemical relationships that must be maintained. Then replacement of some nonessential amino acids by non-natural amino acids, with the d-amino acid isomer, or with peptide-bond isosteres may be suffcient to block degradation by proteases. Other strategies include replacement of specifc the amino acids with the N-methyl derivatives, with topographically constrained derivatives, or with the halogenated derivatives of aromatic amino acids. Finally, the use of the “multiple-antigenic-peptide” approach where many molecules are attached to a carrier with multiple attachment points can produce molecules that, due to their size, are not recognized by proteases. This chapter emphasizes the role of creative synthetic chemistry is the modifcation of peptides to achieve stability and bioavailability.
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The simulated batches follow normal distribution with a certain standard deviation (indicated along the X-axis). The curriculum is designed to foster offers micronization and mechanical milling industry. The company supplies products and professional development in areas such as in isolated processing suites. Its analytical services to approximately 300 of the world’s aseptic processing, biotechnology, environ- laboratory provides material-characterization leading pharmaceutical and biotechnical mental monitoring, filtration, microbiology, testing, including particle size and Karl Fischer companies. Patheon’s fully integrated world- quality, regulatory affairs, training, and vali- moisture analysis. Courses can be customized and pro- method development and validation and re- products can be launched anywhere in the vided at the client’s location. Pfizer CentreSource provides solutions for sterile manufac- turing, high-con- Hospira’s One 2 One business specializes in Metrics is a respected contract pharmaceuti- tainment manufac- contract manufacturing of injectable prod- cal research, formulation, development, and turing, and oral and ucts packaged in vials, prefilled syringes, manufacturing company. Gram and kilogram ing, oral drug delivery, and contract manu- quantities as high as 100 kg thus can be mi- facturing. The research described in this thesis was performed at the Division of Medicinal Chemistry of the Leiden/Amsterdam Center for Drug Research, Leiden University (Leiden, The Netherlands). Substructure-Based Virtual Screening for Adenosine A2A Receptor Ligands 145 Chapter 6. General Conclusion and Perspectives 215 Summary 227 Samenvatting 230 List of publications 235 Curriculum Vitae 237 Nawoord 239 Abbreviations 241 7 General Introduction This thesis is about drug discovery and how the computer can assist in this lengthy and costly process. As I will explain in the paragraphs below it still makes good sense today as it did in the past to have a closer look at the chemical structure of drugs, and in particular to elements or fragments in these chemical structures. Therefore, I should like to start my thesis with some thoughts on drugs and drug discovery per se and how developments in informatics and computer science offer new opportunities. It has evolved from early serendipitous discovery from natural sources, such as morphine from poppy seeds, to 1, 2 today’s industrial-scale screening projects. Modern drug discovery starts with the identification of a biological target that can be modulated to induce the desired therapeutic effect. To search for potential drugs, compounds are tested for their ability to modulate the target. However, even though screening capacity reaches millions of compounds and continues to grow, the number of possible molecules that could be synthesized and tested is infinitely larger. This notion has important consequences; apparently, we can only test a tiny sample of what is virtually available. Chemical space can be traversed by means of chemical transformations, which start from one point in chemical space, i. These transformations are either hypothetical modifications of the molecular structure or synthetic chemical reactions. While ‘travelling’ from one molecule to another takes place by chemical transformations, a clear account on the dimensionality of chemical space or the axes along which is travelled cannot be given. The choice of properties depends on the purpose of the chemical space representation, for instance, whether the aim is to analyze distribution of a set of molecules in chemical space or whether the aim is to 11 Chapter 1 extrapolate to find molecules with better properties. Defining axes in chemical space facilitates distance measurement between molecules, an important concept in cheminformatics. Chemical space is infinite; however, by putting limits on the size of the molecules that are considered, estimates of the number of molecules in chemical space can be made. For instance, when restricting to small organic molecules, size estimates range from 20 60 3, 4 10 to more than 10 molecules, a number for which there would not be sufficient matter in the universe to synthesize all. The number of known organic and inorganic molecules fades when considering the number of theoretical possibilities. While it is impossible to synthesize all possible (small) molecules, it is feasible to construct and explore a virtual chemical space with the aid of the computer. However, a systematic enumeration of all possible organic molecules (with constrained size and type) was first carried out 7 by Fink et al. Mapping compounds from known ‘physical’ compound databases onto this chemical space indicated large unexplored areas. Later, the same group reported the subsequent construction of a database of all feasible organic molecules that consisted of up to 13 atoms of the elements carbon, nitrogen, 8 oxygen, sulfur, and chlorine. Note that both databases consist of drug-like compounds only, according to Lipinski’s rule of five. This rule states that for a compound to be orally absorbed it should have not more than five hydrogen bond 12 General Introduction donors, not more than 10 hydrogen bond acceptors, a molecular weight below 500 Daltons, and a calculated octanol-water partitioning coefficient (logP) not higher than 9 5. Even if it were possible to synthesize all molecules in chemical space, this would not be desirable since most of the molecules would not have any wanted activity, and thus be a waste of materials and resources. Instead of considering all possible molecules in chemical space, one should attempt to select only those molecules that possess the desired properties. To find the desired molecules from chemical space, computational techniques are needed to predict the properties of the virtual molecules. This often implies knowledge of the target, usually a protein, too to find new ligands (i. These ligands do not necessarily originate from a design process but can also stem from virtual screening of compound libraries. Virtual screening represents the computational counterpart of high-throughput screening. Instead of the physiological target, a computational model that represents the target is used to identify hits. Two main approaches exist in rational drug design: structure-based approaches and ligand-based approaches. The structure-based approaches depend on the availability of the three-dimensional structure of the target under study, for instance, the X-ray crystal structure or a suitable homology model. Computer-modeling techniques are then applied to find new ligands, or modify existing ones, that fit into the target structure. In contrast, ligand-based approaches do not require information on the target protein, but instead rely upon the availability of a sufficient amount of 13 Chapter 1 ligand data. Combinations of the two approaches are found in the realm of chemogenomics, which will be discussed later. While structure-based approaches typically place a high demand on computational resources, these allow for the discovery of truly new chemistry. Moreover, structure-based approaches become 10 more feasible with the steady growth of computing power (known as “Moore’s law” ) available to the medicinal chemist. On the other hand, ligand-based virtual screening has been shown to perform often equally well compared to structure-based virtual 11 screening. Finding the desired molecules in chemical space may be accomplished in two distinct ways: first, using selection or prioritization of molecules, and second, by performing a steered search. With selection, molecules with the desired properties are selected (or molecules with undesirable properties are filtered out) from the total set of possible molecules. Prioritization on the other hand, ranks molecules according to the desired properties and selects a certain number of the top-ranked molecules. Note that in practice not the real chemical space is screened; instead, large virtual libraries, or existing libraries of commercially available or in-house compounds are screened. The second approach to find the desired molecules is exploration of chemical space by performing a steered search. With this approach, a ‘walk’ is conducted along neighboring molecules in the direction of molecules with properties that are more favorable. Neighboring molecules are molecules that can be transformed into one another by modifications of the chemical structure. The general principle is to move gradually towards better molecules by repeatedly selecting the best neighboring molecule as the next ‘step’. The process is comparable to what medicinal chemists do to search for molecules with improved properties by synthesizing a set of derivatives from a starting structure. However, with a steered search in chemical space, the properties of the virtual molecules are predicted by computational methods.