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Nuclear Receptors as Drug Targets, Volume 39

Eckhard Ottow (Editor), Hilmar Weinmann (Editor), Raimund Mannhold (Series Editor), Hugo Kubinyi (Series Editor), Gerd Folkers (Series Editor)
ISBN: 978-3-527-31872-8
522 pages
October 2008
Nuclear Receptors as Drug Targets, Volume 39 (3527318720) cover image
Edited by two experts working at the pioneering pharmaceutical company and major global player in hormone-derived drugs, this handbook and reference systematically treats the drug development aspects of all human nuclear receptors, including recently characterized receptors such as PPAR, FXR and LXR. Authors from leading pharmaceutical companies around the world present examples and real-life data from their own work.
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List of Contributors XV

Preface XIX

A Personal Foreword XXI

1 Nuclear Receptors as Drug Targets: A Historical Perspective of Modern Drug Discovery 1
Eckhard Ottow and Hilmar Weinmann

1.1 Introduction 1

1.2 Short Historical Overview on Nuclear Receptors in Pharmacological Research and Drug Discovery 1

1.3 Recent Progress in Nuclear Receptor Drug Discovery 9

1.4 Modern Methods and Technologies in Nuclear Receptor Drug Discovery 13

1.5 Summary and Future Developments 16

2 Targeting the Nuclear Receptor–Cofactor Interaction 25
Belen Vaz, Sabine Möcklinghoff, and Luc Brunsveld

2.1 Introduction 25

2.2 Evaluation of the Nuclear Receptor–Cofactor Interaction as a Drug Target 28

2.3 Inhibitors of the Nuclear Receptor–Cofactor Interaction 33

2.4 Perspectives 39

3 Untangling the Estrogen Receptor Web: Tools to Selectively Study Estrogen-Binding Receptors 47
Ross V. Weatherman

3.1 Physiological Roles of Estrogen and the Challenges in Drug Discovery 47

3.2 Possibility of Multiple Targets 47

3.3 ERa 48

3.4 ERb 51

3.5 ERR 53

3.6 GPR30 55

3.7 Membrane ERs 57

3.8 Integrated Estrogen Signaling 58

3.9 Conclusions 58

4 Subtype-Selective Estrogens 65
Gerrit H. Veeneman

4.1 Introduction 65

4.2 Subtype-Selective ER Ligands 69

4.3 Conclusions 115

5 Estrogen Receptors as Therapeutic Targets in Breast Cancer 127
Eric A. Ariazi and V. Craig Jordan

5.1 Introduction 127

5.2 Biology of ERs 130

5.3 Therapeutic Basis for Targeting ER 135

5.4 SERMs 136

5.5 Mechanisms of Action of SERMS 144

5.6 Additional SERMs 150

5.7 Pure Antiestrogens 164

5.8 Conclusions 170

6 Progesterone Receptor: Overview of Modern Steroidal Progestins and Developments in the Field of Nonsteroidal Selective Progesterone Receptor Modulators 201
Klaus Schöllkopf and Norbert Schmees

6.1 Introduction 201

6.2 Biology of PR 202

6.3 Structure of the LBD of PR 205

6.4 Steroidal Progestins 206

6.5 Nonsteroidal Progestins 209

6.6 Conclusions and Outlook 218

7 Progesterone Receptor Antagonists 223
Irving M. Spitz

7.1 Introduction 223

7.2 Chemistry 223

7.3 Progesterone Receptor (PR) 225

7.4 Mechanism of Action 226

7.5 Biological Effects of PAs and SPRMs 229

7.6 Clinical Applications 231

7.7 Other Potential Obstetrical and Gynecological Applications 235

7.8 Nongynecological Applications 236

7.9 Side-Effects of Long-Term Administration of PAs and SPRMs 238

7.10 Conclusions 240

8 Nonsteroidal Tissue-selective Androgen Receptor Modulators 249
Michael L. Mohler, Casey E. Bohl, Ramesh Narayanan, Yali He, Dong Jin Hwang, James T. Dalton, and Duane D. Miller

8.1 Introduction 249

8.2 Nonsteroidal AR Ligands 255

8.3 Molecular Basis for SARM Activities 276

8.4 SARMs: A Promising Class of Clinical and Preclinical Candidates 283

9 Novel Glucocorticoid Receptor Ligands 305
Heike Schäcke, Khusru Asadullah, Markus Berger, and Hartmut Rehwinkel

9.1 Introduction 305

9.2 GR and its Action 307

9.3 Selective Modulation of GR Activities 310

9.4 Dissociated GR Ligands 311

9.5 Conclusions and Perspectives 319

10 1,25-Dihydroxyvitamin D3 and its Dissociated Analogs as Modulators of Vitamin D Receptor Action 325
Ekkehard May, Andreas Steinmeyer, Khusru Asadullah, and Ulrich Zügel

10.1 Introduction 325

10.2 Principles of Cellular and Molecular Action of Vitamin D 326

10.3 Mechanisms of Vitamin D3-Mediated Immunomodulation 331

10.4 Effects of 1,25(OH)2D3 In Vivo and Clinical Implications 338

10.5 Dissociated Vitamin D Derivatives 345

10.6 Calcitriol Derivatives with Heterocyclic Units in the Side-Chain 346

10.7 Conclusions 353

11 Peroxisome Proliferator-Activated Receptor g Modulation for the Treatment of Type 2 Diabetes 367
Alan M. Warshawsky and Anne Reifel Miller

11.1 Introduction 367

11.2 Currently Marketed PPARg Ligands 373

11.3 Approaches to Improve PPARg Activity 375

11.4 Discussion and Summary 381

11.5 Future Direction 382

12 Retinoids in Clinical Use 389
Vincent C. O. Njar

12.1 Introduction 389

12.2 Mechanism of Action of Retinoids and Retinoic Acids 389

12.3 Retinoids and Rexinoids in the Clinic 392

12.4 Development of New Retinoids/Rexinoids and the Future for Retinoid-based Therapies 398

12.5 Conclusions 399

13 Nuclear Receptors as Targets in Cardiovascular Diseases 409
Peter Kolkhof, Lars Bärfacker, Alexander Hillisch, Helmut Haning, and Stefan Schäfer

13.1 Introduction 409

13.2 MR (NR3C2) 409

13.3 THRs (NR1A1 and NR1A2) 414

13.4 PPARa (NR1C1) 418

13.5 VDR (NR1I1) 421

13.6 Retinoic Acid Receptors (NR1B1, 2 and 3) and Retinoid X Receptors (NR2B1, 2 and 3) 422

13.7 Liver X Receptors (NR1H3 and NR1H2) 422

13.8 Outlook 423

14 NR4A Subfamily of Receptors and their Modulators 431
Henri Mattes

14.1 Introduction 431

14.2 Functions of NR4A Receptor Subfamily 431

14.3 Structures of NR4A1 and NR4A2 435

14.4 Modulators of the NR4A Subfamily 436

14.5 Conclusions and Outlook 443

15 Induction of Drug Metabolism: Role for Nuclear Receptors 453
Christoph Handschin

15.1 Introduction 453

15.2 PXR: Structure and Activation 453

15.3 CAR: Structure and Activation 454

15.4 Detoxification of Drugs and Other Xenobiotics 455

15.5 PXR and CAR Regulation of Bile Acid, Cholesterol and Bilirubin Metabolism 456

15.6 Xenobiotic-Sensing Nuclear Receptors in Cancer, Oxidative Stress and Pollution 456

15.7 CAR and PXR in Inflammation 457

15.8 Regulation of Glucose and Lipid Homeostasis by CAR and PXR 457

15.9 Conclusions and Perspectives 458

16 Designing Chemical Libraries Directed to Nuclear Receptors 469
Elisabet Gregori-Puigjané and Jordi Mestres

16.1 Introduction 469

16.2 Collecting and Storing Prior Knowledge 470

16.3 Nuclear Receptor Profiling 474

16.4 New Trends in Designing Targeted Libraries 480

16.5 Conclusions and Outlook 485

References 486

Index 489

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Eckard Ottow is the head of medicinal chemistry at Schering AG in Berlin (Germany). He studied Chemistry at the University of Hannover (Germany) and received his PhD degree in 1982. He joined Schering AG in 1983, first in the field of endocrinology and later in oncology and CNS. In 2002, he was appointed to his present position as head of medicinal chemistry. He is also a honorary professor at the Technical University of Berlin.

Hilmar Weinmann studied Chemistry at the universities of Tübingen and Hannover (Germany). He joined Schering in 1995, where he is currently a department head of Medicinal Chemistry. His main fields of expertise are in oncology, dermatology and gender healthcare.
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"With increasing importance attributed to this area, the text is a welcome review of the current field.... The quality of the text is good with very readable chapters and many useful original literature references. The book will be clearly valuable for both academic and industrial groups engaged in drug discovery." (Journal of Medicinal Chemistry, March 2009)

"This is an excellent book for scientists interested in adding or expanding expertise in nuclear receptor drug discovery to their skill set. The chapters are timely, well referenced into the 2008 literature, and focused on the chemistry of successful and emerging therapeutic small molecules." (Journal of the American Chemical Society, March 10, 2009)

"The book is a good reference for medicinal chemists, pharmacologists and those working in the pharmaceutical industry." (RoSearch, December 2008)

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