Lawton Progress in Medicinal Chemistry

1. Auflage 2015
ISBN: 978-0-444-63485-6
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 54, 314 Seiten

Reihe: Progress in Medicinal Chemistry

Progress in Medicinal Chemistry provides a review of eclectic developments in medicinal chemistry. This volume includes chapters covering recent advances in cancer therapeutics,ÿÿfluorine in medicinal chemistry, aÿ perspective on the next generation of antibacterial agents derived by manipulation of natural products, aÿ new era for Chagas Disease drug discovery? and imaging in drug development. - Extended timely reviews of topics in medicinal chemistry - Targets and technologies relevant to the discovery of tomorrow's drugs - Analyses of successful drug discovery programmes

Autoren/Hrsg.

Lawton, G.

Inhaltsverzeichnis

1;Front Cover;1
2;Progress in Medicinal Chemistry;4
3;Copyright;5
4;Contents;6
5;Contributors;8
6;Preface;10
7;Chapter 1: Recent Advances in Cancer Therapeutics;14
7.1;1. Introduction;14
7.2;2. Chaperone Inhibitors;15
7.3;3. Kinase Inhibitors;25
7.3.1;3.1. Introduction;25
7.3.2;3.2. Vemurafenib-An Inhibitor Targeting a Mutated Kinase;36
7.3.3;3.3. Ibrutinib-A Covalent, Irreversible Inhibitor;39
7.3.4;3.4. Tumour Resistance to Kinase Inhibitors;43
7.4;4. HDAC Inhibitors;45
7.4.1;4.1. Introduction to Histone Deacetylases;45
7.4.2;4.2. Histone Deacetylase Inhibitors;46
7.4.2.1;4.2.1. Biological Activity;47
7.4.2.2;4.2.2. Hydroxamic Acids;49
7.4.2.3;4.2.3. Cyclic Tetrapeptides;51
7.4.2.4;4.2.4. Benzamides;52
7.4.2.5;4.2.5. Aliphatic Acids;53
7.4.2.6;4.2.6. HDAC Class-Selective Inhibitors;53
7.4.2.7;4.2.7. Histone Deacetylase Inhibitors as Part of Single Agent Therapies;54
7.4.2.8;4.2.8. Histone Deacetylase Inhibitors as Part of Combinatorial Therapies;54
7.5;5. Inhibitors of Protein-Protein Interactions (PPIs);54
7.5.1;5.1. Background;54
7.5.2;5.2. BCL-2/BH3-Domain Small-Molecule Inhibitors;55
7.5.3;5.3. Inhibiting P53/MDM2 Interaction;59
7.5.4;5.4. Rapalogs as Allosteric PPI Inhibitors;62
7.6;References;67
8;Chapter 2: Fluorine in Medicinal Chemistry;78
8.1;1. Introduction;79
8.2;2. Survey of Fluorine Chemotypes in Marketed Drugs;80
8.3;3. Impact of Fluorine on Lipophilicity;82
8.3.1;3.1. Aromatic Systems;82
8.3.2;3.2. Aliphatic Systems;84
8.4;4. Impact of Fluorine on pKa;86
8.4.1;4.1. pKa Modulation and Brain Penetration;91
8.4.2;4.2. pKa Modulation and Cell Potency;92
8.4.3;4.3. pKa Modulation and Reducing hERG Activity;93
8.5;5. Impact of Fluorine on Metabolism;96
8.5.1;5.1. Aromatic Ring Oxidation;96
8.5.2;5.2. Aliphatic Oxidation;99
8.6;6. Metabolism to Toxic Metabolites;101
8.7;7. Fluorine Interactions in Proteins;104
8.8;8. Conformational Influences of Fluorine;107
8.8.1;8.1. Influence on Geometry at Carbon;107
8.8.2;8.2. Charge-Dipole Interactions;109
8.8.3;8.3. Hyperconjugation;110
8.8.4;8.4. Dipole-Dipole Interactions;113
8.9;9. Marketed Drug Case Studies;114
8.9.1;9.1. Ezetimibe (Zetia TM);114
8.9.2;9.2. Celecoxib (Celebrex TM);116
8.9.3;9.3. Sitagliptin (Januvia TM);118
8.9.3.1;9.3.1. Impact of Fluorine on Pharmacology Profile;119
8.9.3.2;9.3.2. Contribution of Fluorine to Pharmacokinetic Profile;120
8.9.3.3;9.3.3. Structural Aspects;123
8.9.3.4;9.3.4. Contribution of Fluorine to Safety Profile;125
8.9.4;9.4. Fluconazole (Diflucan TM) and Voriconazole (Vfend TM);125
8.9.5;9.5. Fluoroquinolones;128
8.9.6;9.6. Fluticasone Propionate (Flovent TM, Flixotide TM);131
8.9.6.1;9.6.1. Structural Aspects;133
8.9.7;9.7. Aprepitant (Emend TM);135
8.10;10. Summary and Future Outlook;138
8.11;References;139
9;Chapter 3: A Perspective on the Next Generation of Antibacterial Agents Derived by Manipulation of Natural Products;148
9.1;1. Introduction;148
9.2;2. Glycopeptides;150
9.3;3. Tetracyclines;156
9.4;4. Aminoglycosides;163
9.5;5. Ketolides;170
9.6;6. Thiazolyl Peptides;174
9.7;7. Pleuromutilins;179
9.8;8. Polymyxins;184
9.9;9. Conclusion;191
9.10;References;191
10;Chapter 4: A New Era for Chagas Disease Drug Discovery?;198
10.1;1. Introduction;198
10.2;2. Benznidazole as Historic Anti-Chagasic Chemotherapy;200
10.3;3. CYP51 as a Drug Target for T. cruzi Growth Inhibition;202
10.4;4. Clinical Trials;204
10.5;5. Evolution of Screening Cascades;209
10.6;6. Compound Landscape for Chagas Disease Chemotherapies;214
10.6.1;6.1. T. cruzi CYP51 Inhibitors;214
10.6.2;6.2. T. cruzi CYP51 Inhibitors in Abundance?;217
10.6.3;6.3. Other Points of Intervention in the Sterol Biosynthesis Pathway;219
10.6.4;6.4. Is There a Future for Nitro Heterocycles?;220
10.6.4.1;6.4.1. Fexinidazole;220
10.6.4.2;6.4.2. Other Nitro Heterocycles;221
10.6.5;6.5. Compounds from Phenotypic Screens Without Target Information;222
10.6.6;6.6. Established Drug Targets;225
10.6.7;6.7. Emerging Drug Targets;227
10.6.7.1;6.7.1. Sirtuins;227
10.6.7.2;6.7.2. UDP-Galctopyranose Mutase;228
10.6.7.3;6.7.3. Phosphofructokinase;229
10.6.7.4;6.7.4. N-myristoyltransferase;229
10.6.7.5;6.7.5. Carbonic Anhydrase;229
10.6.8;6.8. Drug Re-purposing Efforts;230
10.7;7. Summary;233
10.8;References;234
11;Chapter 5: Imaging in Drug Development;244
11.1;1. Introduction;244
11.2;2. Magnetic Resonance Imaging;246
11.2.1;2.1. Use of MRI in the Clinic;247
11.2.2;2.2. MRI in Drug Development;249
11.2.2.1;2.2.1. Oncology;249
11.2.2.1.1;2.2.1.1. Dynamic Contrast Enhancement;249
11.2.2.1.2;2.2.1.2. Diffusion Weighted Imaging;250
11.2.2.2;2.2.2. Central Nervous System;250
11.2.2.2.1;2.2.2.1. Functional MRI;251
11.3;3. Nuclear Medicine Imaging;252
11.3.1;3.1. Single-Photon Emission Computed Tomography;252
11.3.1.1;3.1.1. Technetium-99m Tracers;253
11.3.1.2;3.1.2. Indium-111 Tracers;255
11.3.1.3;3.1.3. Iodine-123 Tracers;255
11.3.1.4;3.1.4. Applications of SPECT to Translational Medicine;257
11.3.2;3.2. Positron Emission Tomography;259
11.3.2.1;3.2.1. Carbon-11 Tracers;260
11.3.2.2;3.2.2. Fluorine-18 Tracers;263
11.3.2.2.1;3.2.2.1. Preparation of [18F]Fluoroalkanes;265
11.3.2.2.2;3.2.2.2. Preparation of [18F]Fluoroarenes;267
11.3.2.2.3;3.2.2.3. Labelling of Peptides and Proteins with Fluorine-18;271
11.3.2.3;3.2.3. Iodine-124 Tracers;274
11.3.2.4;3.2.4. Zirconium-89 Tracers;277
11.3.2.5;3.2.5. Copper-64 Tracers;278
11.3.2.6;3.2.6. Gallium-68 Tracers;280
11.3.2.7;3.2.7. Application of PET to Translational Medicine;281
11.4;4. Summary and Future Prospects;284
11.5;References;285
12;Subject Index;294
13;Cumulative Index of Authors for Volumes 1–54;302
14;Cumulative Index of Subjects for Volumes 1–54;308

Leseproben

Chapter One Recent Advances in Cancer Therapeutics
Nicola Chessum; Keith Jones; Elisa Pasqua; Michael Tucker    Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, London, United Kingdom Abstract
In the past 20 years, cancer therapeutics has undergone a paradigm shift away from the traditional cytotoxic drugs towards the targeting of proteins intimately involved in driving the cancer phenotype. The poster child for this alternative approach to the treatment of cancer is imatinib, a small-molecule kinase inhibitor designed to target chronic myeloid leukaemia driven by the BCR–ABL translocation in a defined patient population. The improvement in survival achieved by treatment of this patient cohort with imatinib is impressive. Thus, the aim is to provide efficacy but with low toxicity. The role of the medicinal chemist in oncology drug discovery is now closely aligned with the role in most other therapeutic areas with high-throughput and/or fragment-based screening, structure-based design, selectivity, pharmacokinetic optimisation and pharmacodynamic biomarker modulation, all playing a familiar part in the process. In this chapter, we selected four areas in which compounds are either approved drugs or in clinical trials. These are chaperone inhibitors, kinase inhibitors, histone deacetylase inhibitors and inhibitors of protein–protein interactions. Even within these areas, we have been selective, particularly for kinase inhibitors, and our aim has been to exemplify newer approaches and novel aspects of medicinal chemistry. Keywords Cancer therapeutics Personalised medicine Chaperones Kinase inhibitors Protein–protein interactions Histone deacetylases Epigenetics 1 Introduction
In the past 20 years, cancer therapeutics has undergone a paradigm shift away from the traditional cytotoxic drugs towards the targeting of proteins intimately involved in driving the cancer phenotype [1]. The poster child for this alternative approach to the treatment of cancer is imatinib, a small-molecule kinase inhibitor designed to target chronic myeloid leukaemia driven by the BCR–ABL translocation in a defined patient population [2]. The improvement in survival achieved by treatment of this patient cohort with imatinib is impressive. Thus, the aim is to provide efficacy but with low toxicity. The role of the medicinal chemist in oncology drug discovery is now closely aligned with the role in most other therapeutic areas with high-throughput and/or fragment-based screening, structure-based design, selectivity, pharmacokinetic optimisation and pharmacodynamic biomarker modulation, all playing a familiar part in the process. In a short review of this nature covering such a large and active field, we have had to be selective in our choices of examples. We have chosen four areas in which compounds are either approved drugs or in clinical trials. These are chaperone inhibitors, kinase inhibitors, histone deacetylase inhibitors and inhibitors of protein–protein interactions (PPIs). Even within these areas, we have had to be selective, particularly for kinase inhibitors, and we have tried to exemplify newer approaches and novel aspects of medicinal chemistry. 2 Chaperone Inhibitors
Although the targeting of oncogenic proteins such as kinases has led to significant clinical benefit over the last 15 years, expectations have outweighed the reality in terms of outcomes. There are many reasons for this including tumour heterogeneity, intrinsic and acquired drug resistance and the presence of multiple oncogenic drivers in any single cancer. Targeting the cellular machinery responsible for protein quality control provides a more wide-ranging, yet still targeted, approach to inhibiting oncogenic proteins. Proteins consist of an elaborate arrangement of folds and secondary structure and, although many aspects of the folding are inherent in the properties of the protein itself, the process is complex and errors occur [3]. Indeed, the final, stable structure is often characterised by a free energy gain of some 3–7 kcal/mol over a range of partially misfolded states [4]. In a crowded cellular environment, correct protein folding is made even more difficult because of collisions between protein molecules [5]. Cells have developed a number of mechanisms to cope with ensuring that correct protein conformations are maintained. In the nuclear and cytosolic compartments, the heat-shock response, involving a range of heat-shock proteins (HSPs), is a conserved mechanism for dealing with misfolded proteins. Originally thought to be an emergency response to sudden stress, it is now recognised to be a constant process enabling protein homeostasis. In the context of cancer cells, the heat-shock response is a vital method of maintaining protein function in the stressed oncogenic state, and targeting this response may provide a combinatorial blockade of multiple oncogenic proteins. Heat-shock protein 90 (HSP90) is a member of the high molecular weight HSPs, along with HSP70. It accounts for some 1–2% of all cellular protein [6], and there are four closely homologous, important isoforms: HSP90a and HSP90ß which are cytosolic, GRP94 which is found in the endoplasmic reticulum and TRAP1 found in mitochondria. HSP90 has a long list of client proteins that include a number of key oncogenes such as ERBB2, RAF and the androgen receptor [7]. Active HSP90 is a homodimer with each monomer consisting of an N-terminal ATP-binding domain, a middle domain and a C-terminal dimerisation domain. Seminal crystallographic studies by the Pearl group identified the ATP-binding pocket of HSP90 [8] and provided strong evidence for a catalytic cycle driven by ATP hydrolysis [9]. A variety of co-chaperones have been identified as playing roles in the catalytic cycle but HSP90 remains the key effector (Figure 1). Figure 1 (A) ADP bound to the nucleotide domain of HSP90 (PDB: 1BYQ). (B) A schematic view of the HSP90 catalytic cycle showing the N-terminal domain (NTD), C-terminal dimerisation domain (CTD) and the various co-chaperones that are involved at each stage. The first HSP90 inhibitors to be recognised were the natural products, geldanamycin (1) and radicicol (2). Geldanamycin is a benzoquinone ansamycin isolated from a Streptomyces species and was originally thought to be a tyrosine kinase inhibitor. In 1994, it was shown to bind to HSP90 [10], and this was followed in 1999 by a co-crystal structure of geldanamycin bound to the N-terminal domain of HSP90 [11]. Structurally, the ATP-binding pocket of HSP90 belongs to the unusual Bergerat fold class of ATP-binding sites that is shared by relatively few proteins [12]. The co-crystal structure of the HSP90 N-terminal domain and geldanamycin is both interesting and informative. The ligand adopts a folded conformation in its bound state in which the benzoquinone ring folds back over the macrocycle with the benzoquinone at the top (open) part of the pocket. There are a number of water-mediated hydrogen bond interactions between the ligand and the protein, a feature of all ligands that bind HSP90 in this pocket including the natural ligands ATP and ADP (Figure 2). Figure 2 (A) X-ray crystal structure of geldanamycin bound to the N-terminal domain of HSP90 (PDB: 1YET). (B) Structures of natural product and semi-synthetic inhibitors of HSP90. Geldanamycin shows not only potent in vitro and in vivo antitumour activity but also severe hepatotoxicity in preclinical animal models. It also has poor physicochemical properties including solubility, and owing to its benzoquinone moiety, it is a substrate for NQ01: a quinone reductase that converts the parent quinone to the more active hydroquinone. Semi-synthetic derivatives of geldanamycin have addressed the solubility issues. The two successful ones are 17-allyaminogeldanamycin (17-AAG, 3) and 17-dimethylaminoethylgeldanamycin (17-DMAG, 4) in which the 17-methoxy group of the quinone has been replaced by the appropriate amino group in a simple addition–elimination reaction. Following promising anticancer activity in preclinical models [13], 17-AAG (tanespimycin) entered clinical trials in 1999 (administered intravenously), and evidence of clinical activity was seen in a variety of cancers as a single agent and in combination [14] but its development was stopped after Phase II trials owing to formulation and patent life issues. The greater solubility of 17-DMAG (alvespimycin) allowed easier formulation, and a complete response was reported following i.v. administration as a single agent in castration-refractory prostate cancer in a Phase I/II trial [15]. Again, clinical investigations have been halted owing to toxicity issues [16]. The only significant alternative approach to address the issues with geldanamycin and its derivatives was by Infinity Pharmaceuticals who prepared the hydroquinone hydrochloride salt of 17-AAG, designated IPI-504 or retaspimycin hydrochloride. Following initial positive results in a Phase II trial, it has now been withdrawn owing to toxicity [17]. The second natural product, radicicol, is an extremely potent inhibitor of HSP90...