Analogue-based drug discovery (Weinheim, 2006). - ОГЛАВЛЕНИЕ / CONTENTS
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ОбложкаAnalogue-based drug discovery / ed. by Fischer J., Ganellin C.R. - Weinheim: Wiley-VCH, 2006. - 557 p. - ISBN 978-3-527-31257-3
 

Оглавление / Contents
 
Preface ...................................................... XVII
Introduction .................................................. XIX
List of Contributors .......................................... XXV
Abbreviations ................................................ XXIX

Part I.  General Aspects of Analogue-Based Drug Discovery ....... 1

1.  Analogues as a Means of Discovering New Drugs ............... 3
       Camille С Wermuth
    1.1.  Designing of Analogues ................................ 3
          1.1.1.  Analogues Produced by Homologous Variations ... 3
                  1.1.1.1.  Homology Through Monoalkylation ..... 3
                  1.1.1.2.  Polymethylenic Bis-Ammonium
                            Compounds: Hexa- and
                            Decamethonium ....................... 3
                  1.1.1.3.  Homology in Cyclic Compounds ........ 4
          1.1.2.  Analogues Produced by Vinylogy ................ 4
                  1.1.2.1.  Zaprinast Benzologues ............... 5
          1.1.3.  Analogues Produced by Isosteric Variations .... 5
                  1.1.3.1.  The Dominant Parameter is
                            Structural .......................... 5
                  1.1.3.2.  The Dominant Parameter is
                            Electronic .......................... 6
                  1.1.3.3.  The Dominant Parameter is
                            Lipophilicity ....................... 7
          1.1.4.  Positional Isomers Produced as Analogues ...... 7
          1.1.5.  Optical Isomers Produced as Analogues ......... 8
                  1.1.5.1.  Racemic Switches .................... 8
                  1.1.5.2.  Specific Profile for Each
                            Enantiomer .......................... 8
          1.1.6.  Analogues Produced by Ring Transformations .... 9
          1.1.7.  Twin Drugs .................................... 9
    1.2.  The Pros and Cons of Analogue Design ................. 10
          1.2.1.  The Success is Almost Warranted .............. 10
          1.2.2.  The Information is Available ................. 11
          1.2.3.  Financial Considerations ..................... 11
          1.2.4.  Emergence of New Properties .................. 12
    1.3.  Analogue Design as a Means of Discovering
          New Drugs ............................................ 12
          1.3.1.  New Uses for Old Drugs ....................... 12
          1.3.2.  The PASS Program ............................. 14
          1.3.3.  New Leads from Old Drugs: The SOSA
                  Approach ..................................... 14
                  1.3.3.1.  Definition ......................... 14
                  1.3.3.2.  Rationale .......................... 15
                  1.3.3.3.  Availability ....................... 15
                  1.3.3.4.  Examples ........................... 15
                  1.3.3.4.  Discussion ......................... 18
    1.4.  Conclusion ........................................... 20

2.  Drug Likeness and Analogue-Based Drug Discovery ............ 25
       John R. Proudfoot

3.  Privileged Structures and Analogue-Based Drug Discovery .... 53
       Hugo Kubinyi
    3.1.  Introduction ......................................... 53
    3.2.  Drugs from Side Effects .............................. 54
    3.3.  Agonists and Antagonists ............................. 55
    3.4.  Privileged Structures ................................ 57
    3.5.  Drug Action on Target Classes ........................ 58
          3.5.1.  GPCR Ligands ................................. 59
          3.5.2.  Nuclear Receptor Ligands ..................... 61
          3.5.3.  Integrin Ligands ............................. 61
          3.5.4.  Kinase Inhibitors ............................ 63
          3.5.5.  Phosphodiesterase Inhibitors ................. 64
          3.5.6.  Neurotransmitter Uptake Inhibitors ........... 65
    3.6.  Summary and Conclusions .............................. 65

Part II.  Selected Examples of Analogue-Based Drug
          Discoveries .......................................... 69

1.  Development of Anti-Ulcer H2-Receptor Histamine
    Antagonists ................................................ 71
       C. Robin Canellin
    1.1.  Introduction ......................................... 71
    1.2.  The Prototype Drug, Burimamide, Defined Histamine
          H2-Receptors ......................................... 71
    1.3.  The Pioneer Drug, Cimetidine: A Breakthrough for
          Treating Peptic Ulcer Disease ........................ 72
    1.4.  Ranitidine: The First Successful Analogue of H2
          Antagonists .......................................... 73
    1.5.  The Discovery of Tiotidine and Famotidine ............ 76
    1.6.  Other Compounds ...................................... 77
    1.7.  The Use of H2-Receptor Histamine Antagonists as
          Medicines ............................................ 78

2.  Esomeprazole in the Framework of Proton-Pump Inhibitor 
    Development ................................................ 81
       Per Lindberg and Enar Carlsson
    2.1.  Towards Omeprazole: The First Proton-Pump
          Inhibitor ............................................ 81
    2.2.  The Treatment of Acid-Related Disorders Before
          Losec® ............................................... 81
    2.3.  Pioneer Research at Hassle during the 1960s and
          1970s ................................................ 83
          2.3.1.  Toxicological Challenges ..................... 86
          2.3.2.  Discovery of H+, K+-ATPase: The Gastric
                  Proton Pump .................................. 87
          2.3.3.  Analogue Optimization ........................ 87
    2.4.  The Development of Omeprazole ........................ 89
          2.4.1.  Further Toxicological Challenges and the
                  Halt of the Clinical Program ................. 89
          2.4.2.  Resumption of Clinical Studies ............... 90
          2.4.3.  Omeprazole Reaches the Market and
                  Supersedes H2-Receptor Antagonists ........... 90
    2.5.  The Unique Action of Omeprazole ...................... 91
          2.5.1.  Inhibition of the Final Step ................. 91
          2.5.2.  Omeprazole Binds Strongly to the
                  H+, K+-ATPase ................................ 91
          2.5.3.  Inhibition of Acid Secretion and
                  H+, K+-ATPase Activity ....................... 92
          2.5.4.  Omeprazole Concentrates and Transforms
                  in Acid ...................................... 93
          2.5.5.  Disulfide Enzyme-Inhibitor Complex on the
                  Luminal Side ................................. 93
          2.5.6.  Short Half-Life in Plasma and Long Half-
                  Life for Enzyme-Inhibitor Complex ............ 93
          2.5.7.  Mechanism at the Molecular Level ............. 94
          2.5.8.  The "Targeted Prodrug" Omeprazole means a
                  Highly Specific Action ....................... 96

    2.6.  pH-Stability Profile ................................. 97
    2.7.  Omeprazole Analogues Synthesized by Other
          Companies ............................................ 98
    2.8.  Omeprazole: A Need for Improvement? ................. 103
          2.8.1.  The Omeprazole Follow-Up Program ............ 103
          2.8.2.  No Good Alternative to the Omeprazole
                  Structural Template ......................... 103
          2.8.3.  Chemical Approach ........................... 104
          2.8.4.  Synthesis and Screening ..................... 205
          2.8.5.  Isomers Seemed Unattractive ................. 106
          2.8.6.  Isomer Pharmacokinetics and
                  Pharmacodynamics in Animals ................. 106
          2.8.7.  The Key Experiment in Man ................... 107
          2.8.8.  Production of Esomeprazole (Mg Salt) ........ 109
          2.8.9.  Omeprazole Isomers: Differences in
                  Clearance and Metabolic Pattern ............. 109
    2.9.  Summary.............................................. 111

3.  The Development of a New Proton-Pump Inhibitor:
    The Case History of Pantoprazole .......................... 115
       Jörg Senn-Bilfmger and Ernst Sturm
    3.1.  Introduction ........................................ 115
    3.2.  History of Gastrointestinal Research at Byk
          Gulden .............................................. 117
          3.2.1.  The Antacids and Cytoprotectives Projects
                  and the Set-Up of In-Vivo Ulcer Models ...... 117
          3.2.2.  Decision to Concentrate on Anti-Secretory
                  Treatments and the Study of Compounds with
                  an Unknown Mechanism of Action .............. 118
    3.3.  Identification of the First PPI Project
          Candidates .......................................... 121
          3.3.1.  Optimizing the Benzimidazole Moiety ......... 121
          3.3.2.  Impact of the First PPI Project Compounds ... 123
    3.4.  Elucidation of the Mechanism of Action of PPIs ...... 125
          3.4.1.  A Surprising Interrelationship Between
                  Stability and Activity ...................... 125
          3.4.2.  Isolation and Identification of the Active
                  Principle of the PPIs ....................... 125
    3.5.  Identification of Pantoprazole as a Candidate for
          Development ......................................... 128
          3.5.1.  Optimizing the Pyridine Moiety and the
                  First Synthesis of Pantoprazole ............. 128
          3.5.2.  Selection Criteria .......................... 129
          3.5.3.  The Selection of Pantoprazole and Internal
                  Competition with SK&F95601 .................. 130
          3.5.4.  Toxicological Problems: Project
                  Development at Risk ......................... 131
          3.5.5.  Benefits of Pantoprazole for the Patient .... 132
          3.5.6.  Summary ..................................... 132
    3.6.  Outlook on Further Developments ..................... 133

4.  Optimizing the Clinical Pharmacologic Properties of the
    HMC-CoA Reductase Inhibitors .............................. 137
       Sándor Kerpel-Fronius and János Fischer
    4.1.  Introduction ........................................ 137
    4.2.  Medicinal Chemistry of the Statins .................. 138
    4.3.  Clinical and Pharmacologic Properties of the
          Statin Analogues .................................... 142
          4.3.1.  Fibrate Coadministration .................... 148
    4.4.  Clinical Efficacy of the Statins .................... 149

5.  Optimizing Antihypertensive Therapy by Angiotensin
    Receptor Blockers ......................................... 157
       Csaba Farsang and János Fischer
    5.1.  Medicinal Chemistry ................................. 157
    5.2.  Clinical Results with Angiotensin II Antagonists .... 160
          5.2.1.  Mechanisms of Action ........................ 160
                  5.2.1.1.  Other Effects of ARBs ............. 161
          5.2.2.  Target Organ Protection ..................... 162
                  5.2.2.1.  Left Ventricular Hypertrophy ...... 162
                  5.2.2.2.  Diabetic and Nondiabetic
                  Nephropathy ................................. 162
                  5.2.2.3.  Diabetes Prevention ............... 162
                  5.2.2.4.  Coronary Heart Disease (CHD) ...... 162
                  5.2.2.5.  Congestive Heart Failure .......... 162
                  5.2.2.6.  Stroke Prevention and Other
                            CNS Effects ....................... 163
    5.3.  Differences Among Angiotensin AT1 Receptor
          Blockers ............................................ 163
          5.3.1.  Structural Differences ...................... 163
          5.3.2.  AT1 Receptor Antagonism ..................... 164
          5.3.3.  Pharmacokinetics/Dosing Considerations ...... 164
          5.3.4.  Drug Interactions/Adverse Effects ........... 165
          5.3.5.  Efficacy in Hypertension .................... 365
    5.4.  Summary ............................................. 166

6.  Optimizing Antihypertensive Therapy by Angiotensin-
    Converting Enzyme Inhibitors .............................. 169
       Sándor Alföldi and János Fischer
    6.1.  Medicinal Chemistry of ACE-inhibitors ............... 169
    6.2.  Clinical Results with ACE-inhibitors ................ 173
          6.2.1.  Hemodynamic Effects ......................... 173
          6.2.2.  Effects of ACE-inhibitors ................... 174
                  6.2.2.1.  Hypotension ....................... 174
                  6.2.2.2.  Dry Cough ......................... 174
                  6.2.2.3.  Hyperkalemia ...................... 174
                  6.2.2.4.  Acute Renal Failure ............... 175
                  6.2.2.5.  Proteinuria ....................... 175
                  6.2.2.6.  Angioedema ........................ 175
                  6.2.2.7.  Teratogenic Effects ............... 175
                  6.2.2.8.  Other Side Effects ................ 175
          6.2.3.  Contraindications ........................... 176
          6.2.4.  Drug Interactions ........................... 176
    6.3.  Differences Among ACE-inhibitors .................... 177
    6.4.  Summary and Outlook ................................. 179

7.  Case Study of Lacidipine in the Research of New Calcium
    Antagonists ............................................... 181
       Giovanni Gaviraghi
    7.1.  Introduction ........................................ 181
    7.2.  Dihydropyridine Calcium Channel-Blocking Agents ..... 182
          7.2.1.  Nifedipine .................................. 182
          7.2.2.  Felodipine .................................. 183
          7.2.3.  Isradipine .................................. 183
          7.2.4.  Nimodipine .................................. 184
          7.2.5.  Nisoldipine ................................. 184
          7.2.6.  Amlodipine .................................. 185
          7.2.7.  Lacidipine .................................. 185
          7.2.8.  Lercanidipine ............................... 185
          7.2.9.  Manidipine .................................. 186
    7.3.  Lacidipine: A Long-Lasting Calcium Channel-
          Blocking Drug: Case Study ........................... 187
          7.3.1.  The Lacidipine Project ...................... 188
          7.3.2.  Synthesis ................................... 190
          7.3.3.  The Pharmacological Profile of Lacidipine ... 190
    7.4.  Conclusion .......................................... 191

8.  Selective Beta-Adrenergic Receptor-Blocking Agents ........ 193
       Paul W. Erhardt and Lajos Matos
    8.1.  Introduction ........................................ 193
    8.2.  Beta-1 Selective Blockers ........................... 201
          8.2.1.  Atenolol .................................... 201
                  8.2.1.1.  Discovery ......................... 201
                  8.2.1.2.  Synthesis ......................... 203
                  8.2.1.3.  Clinical Pharmacology ............. 203
          8.2.2.  Betaxolol ................................... 206
                  8.2.2.1.  Discovery ......................... 206
                  8.2.2.2.  Synthesis ......................... 209
                  8.2.2.3.  Clinical Pharmacology ............. 210
          8.2.3.  Celiprolol .................................. 211
                  8.2.3.1.  Discovery ......................... 211
                  8.2.3.2.  Synthesis ......................... 214
                  8.2.3.3.  Clinical Pharmacology ............. 215
          8.2.4.  Nebivolol ................................... 217
                  8.2.4.1.  Discovery ......................... 217
                  8.2.4.2.  Synthesis ......................... 218
                  8.2.4.3.  Clinical Pharmacology ............. 220
    8.3.  Accumulated Structure-Activity Relationships ........ 222
    8.4.  Summary ............................................. 226

9.  Case Study: "Esmolol Stat" ................................ 233
       Paul W. Erhardt
    9.1.  Introduction ........................................ 233
    9.2.  Pharmacological Target .............................. 234
    9.3.  Chemical Target ..................................... 234
          9.3.1.  Internal Esters ............................. 234
          9.3.2.  External Esters ............................. 236
          9.3.3.  Structure-Activity Relationships ............ 237
    9.4.  Chemical Synthesis .................................. 240
    9.5.  Pharmacology and Clinical Profile ................... 241
    9.6.  Summary and Some Lessons for Today .................. 243
          9.6.1.  Compound Libraries .......................... 243
          9.6.2.  Biological Testing .......................... 244
          9.6.3.  SAR ......................................... 244

10. Development of Organic Nitrates for Coronary Heart
    Disease ................................................... 247
       László Dézsi
    10.1. Introduction ........................................ 247
    10.2. Empirical Observations Leading to the Therapeutic
          Use of Classic Nitrovasodilators .................... 247
    10.3. Isoamyl Nitrite: The Pioneer Drug ................... 248
    10.4. Nitroglycerin (Glyceryl Trinitrate): The Most
          Successful Analogue ................................. 248
    10.5. Isosorbide Dinitrate: A Viable Analogue with
          Prolonged Action .................................... 249
    10.6. Isosorbide Mononitrate: The Metabolite of
          Isosorbide Dinitrate ................................ 250
    10.7. Nicorandil: The Potassium Channel Opener Analogue
          with a Broad Cardiovascular Spectrum ................ 251
    10.8. Cardiovascular Efficacy of Organic Nitrates ......... 252
    10.9. Mechanism of Action of Organic Nitrates ............. 253
    10.10.Tolerance to Organic Nitrates ....................... 255
    10.11.Concluding Remarks .................................. 256

11. Development of Opioid Receptor Ligands .................... 259
       Christopher R. McCurdy
    11.1. Introduction ........................................ 259
    11.2. Pharmacology Related to the Classic Opioid
          Receptors ........................................... 261
    11.3. Alkaloids from the Latex of Papaver Somniferum
          Initiate Research ................................... 261
    11.4. Morphine: The Prototype Opioid Ligand ............... 262
          11.4.1. Initial Studies of Morphine Analogues ....... 263
    11.5. Structure-Activity Relationships of Morphine
          Derivatives ......................................... 265
    11.6. Synthetic Analogues of Thebaine Further Define
          Morphinan SAR ....................................... 266
    11.7. Compounds of the Morphinan Skeleton Produce
          New Agents .......................................... 269
    11.8. Further Reduction of the Morphinan Skeleton
          Produced the Benzomorphans .......................... 270
    11.9. Another Simplified Version of Morphine Creates
          a New Class of Opioid Ligand ........................ 271
    11.10.A Breakthrough in the Structural Design of
          Opioid Ligands ...................................... 271
    11.11.Discovery of the 4-Anilidopiperidines ............... 273
    11.12.Phenylpropylamines: The Most Stripped-Down
          Opioids Still Related to Morphine ................... 273
    11.13.The Use of Opioid Analgesics in Clinical Practice:
          Hope of the Future .................................. 274

12. Stigmines ................................................. 277
       Zeev Tashma
    12.1. Historical Background ............................... 277
    12.2. Pharmacological Activities of Physostigmine ......... 278
    12.3. Chemistry and Biochemistry of Physostigmine ......... 279
    12.4. Interaction of Acetylcholinesterase with
          Carbamates .......................................... 280
    12.5. SAR of the Eseroline Moiety, and the Development
          of Miotine .......................................... 282
    12.6. The Development of Quaternary Carbamates for
          Myasthenia Gravis ................................... 283
    12.7. Carbamates as Pre-Exposure Treatment against
          Organophosphate Intoxication ........................ 284
    12.8. Carbamates as Insecticides .......................... 286
          12.8.1. Structural Features ......................... 287
    12.9. Carbamates in the Treatment of Alzheimer's
          Disease ............................................. 287
          12.9.2. Close Derivatives of Physostigmine .......... 288
          12.9.3. Rivastigmine ................................ 289

13. Structural Analogues of Clozapine ......................... 297
       Béla Kiss and István Bitter
    13.1. Introduction ........................................ 297
    13.2. Clozapine: The Prototype "Atypical" Antipsychotic;
          Some Chemical Aspects ............................... 299
    13.3. Preclinical Aspects ................................. 300
          13.3.1. Multireceptor Profile: In-Vitro, In-Vivo
                  Similarities and Differences ................ 300
          13.3.2. The Availability of Data .................... 304
          13.3.3. Dopamine D2 versus Serotonin 5-HT2A
                  Affinity .................................... 304
          13.3.4. Affinity to other Receptors ................. 306
          13.3.5. Inverse Agonism ............................. 306
          13.3.6. Receptor Affinity of Metabolites and
                  Clinical Action ............................. 307
    13.4. Clinical Aspects .................................... 307
          13.4.1. Terminology ................................. 307
          13.4.2. Indications ................................. 308
          13.4.3. Dosage ...................................... 308
          13.4.4. Clinical Efficacy in Schizophrenia .......... 308
          13.4.5. Clinical Efficacy in Bipolar Disorder
                  (Especially in Mania) ....................... 309
          13.4.6. Adverse Events .............................. 310
    13.5. Summary and Conclusions ............................. 310

14. Quinolone Antibiotics: The Development of Moxifloxacin .... 315
       Uwe Petersen
    14.1. Introduction ........................................ 315
    14.2. Aims ................................................ 320
    14.3. The Chemical Evolution of Moxifloxacin .............. 321
    14.4. Synthetic Routes .................................... 338
          14.4.1. S,S-2,8-Diazabicyclo[4.3.0]nonane ........... 338
          14.4.2. Preparation of BAY X 8843 36 and its
                  Analogues ................................... 339
          14.4.3. Preparation of Moxifloxacin
                  Hydrochloride 47 ............................ 339
    14.5. The Physicochemical Properties of Moxifloxacin ...... 342
    14.6. The Microbiological and Clinical Properties
          of Moxifloxacin ..................................... 344
          14.6.1. Mycobacterium tuberculosis .................. 347
          14.6.2. Skin Infections ............................. 347
          14.6.3. Ophthalmology ............................... 348
          14.6.4. Dental Medicine ............................. 348
    14.7. Pharmacokinetics/Pharmacodynamics of Moxifloxacin ... 348
    14.8. Development of Resistance to Moxifloxacin ........... 350
    14.9. Safety and Tolerability of Moxifloxacin ............. 352
    14.10.Metabolism, Excretion and Biodegradability of
          Moxifloxacin ........................................ 353
    14.11.Future Prospects for Quinolones ..................... 355
    14.12.Summary and Conclusions ............................. 356

15. The Development of Bisphosphonates as Drugs ............... 371
       Eli Breuer
    15.1. Historical Background ............................... 371
    15.2. Discovery of the Biological Activity of
          Pyrophosphate and of Bisphosphonates ................ 372
    15.3. Bone-Related Activity of Bisphosphonates ............ 372
          15.3.1. Overview .................................... 372
          15.3.2. Osteolytic Bone Diseases .................... 373
                  15.3.2.1. Osteoporosis....................... 373
                  15.3.2.2. Osteolytic Tumors ................. 373
                  15.3.2.3. Paget's Disease ................... 375
          15.3.3. Structure-Activity Relationships ............ 375
                  15.3.3.1. The Molecular Skeletons of
                            Bisphosphonates ................... 375
                  15.3.3.2. Phosphonic Acid Groups ............ 375
                  15.3.3.3. The Geminal Hydroxy Group ......... 375
                  15.3.3.4. Nitrogen-Containing Side Chain .... 375
                  15.3.3.5. Structure-Activity Relationships
                            of BPs: A Summary ................. 376
          15.3.4. Inhibition of Bone Resorption:
                  The Mechanisms of Action .................... 377
          15.3.5. Clinical Pharmacology of Bisphosphonates .... 378
          15.3.6. Bisphosphonates in Clinical Use ............. 379
    15.4. Miscellaneous Biological Aspects of
          Bisphosphonates ..................................... 379
          15.4.1. Bisphosphonates as Vehicles for Delivering
                  Drugs to Bone ............................... 379
          15.4.2. Bisphosphonates as Potential Drugs for
                  other Indications ........................... 379
                  15.4.2.1. Antiviral Drugs ................... 381
                  15.4.2.2. Bisphosphonate Inositol-
                            Monophosphatase Inhibitor:
                            A Potential Drug for Bipolar
                            Disorders ......................... 382
                  15.4.2.3. Hypocholesterolemic 
                            Bisphosphonates (Squalene
                            Synthase Inhibitors) .............. 381
                  15.4.2.4. Antiparasitic Drugs ............... 381
                  15.4.2.5. Anti-Inflammatory and Anti-
                            Arthritic Bisphosphonates ......... 382
                  15.4.2.6. Cardiovascular Applications of
                            Bisphosphonates ................... 382
    15.5. Conclusions ......................................... 382

16. Cisplatin and its Analogues for Cancer Chemotherapy ....... 385
       Sándor Kerpel-Fronius
    16.1. Introduction ........................................ 385
    16.2. Cisplatin ........................................... 385
          16.2.1. Discovery ................................... 385
          16.2.2. Structure ................................... 386
          16.2.3. Mechanism of Action ......................... 386
          16.2.4. Pharmacokinetics ............................ 387
          16.2.5. Clinical Efficacy ........................... 387
          16.2.6. Adverse Effects ............................. 388
    16.3. Carboplatin ......................................... 389
          16.3.1. Development ................................. 389
          16.3.2. Administration and Pharmacokinetics ......... 389
          16.3.4. Adverse Effects ............................. 390
          16.3.5. Clinical Efficacy ........................... 390
    16.4. Oxaliplatin ......................................... 390
          16.4.1. Development ................................. 390
          16.4.2. Cellular Resistance to Various Pt
                  Analogues ................................... 391
          16.4.3. Metabolism and Pharmacokinetics ............. 392
          16.4.4. Adverse Effects ............................. 392
          16.4.5. Clinical Efficacy ........................... 392
    16.5. Summary ............................................. 393

17. The History of Drospirenone ............................... 395
       Rudolf Wiechert
    17.1. General Development ................................. 395
    17.2. Syntheses ........................................... 397

18. Histamine Hn Blockers: From Relative Failures to
    Blockbusters Within Series of Analogues ................... 401
       Henk Timmerman
    18.1. Introduction ........................................ 401
    18.2. The First Antihistamines ............................ 402
    18.3. Diphenhydramine as a Skeleton for Antihistamines .... 403
          18.3.1. The Diaryl Group ............................ 404
          18.3.2. The Linker .................................. 406
          18.3.3. The Basic Group ............................. 406
          18.3.4. The Analogue Principle ...................... 407
          18.3.5. The Analogue Principle in Perspective ....... 409
    18.4. The New Antihistamines .............................. 411
    18.5. Antihistamines for Which the Analogue Principle
          Does not Seem to Work ............................... 415
    18.6. Inverse Agonism ..................................... 415
    18.7. A Further Generation of Antihistamines? ............. 416
    18.8. Conclusions ......................................... 417

19. Corticosteroids: From Natural Products to
    Useful Analogues .......................................... 419
       Zoltán Tuba, Sándor Mahó, and Csaba Sánta
    19.1. Introduction ........................................ 419
    19.2. Corticosteroid Analogues ............................ 420
          19.2.1. Cortisone ................................... 422
          19.2.2. Hydrocortisone .............................. 423
          19.2.3. Prednisone and Prednisolone ................. 424
          19.2.4. Fludrocortisone ............................. 424
          19.2.5. Triamcinolone and Triamcinolone Acetonide ... 425
          19.2.6. Dexamethasone ............................... 426
          19.2.7. Betamethasone ............................... 427
          19.2.8. Beclomethasone Dipropionate ................. 428
          19.2.9. Methylprednisolone .......................... 429
          19.2.10.Fluocinolone Acetonide, Flunisolide,
                  Fluocortin-21-Butylate and Flumetasone ...... 429
          19.2.11.Budesonide .................................. 431
          19.2.12.Halobetasol Propionate ...................... 432
          19.2.13.Mometasone Furoate .......................... 433
          19.2.14.Fluticasone Propionate ...................... 434
          19.2.15.Loteprednol Etabonate ....................... 435
          19.2.16.Ciclesonide ................................. 436
    19.3. Summary ............................................. 437

Part III. Table of Selected Analogue Classes .................. 441
       Erika M. Alapi and János Fischer

Index ......................................................... 553


 
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