Preface ..................................................... XI
List of Contributors ...................................... XIII
Introduction ................................................. 1
1 The Significance of Heterocycles for Pharmaceuticals and
Agrochemicals ................................................ 3
Clemens Lamberth and Jürgen Dinges
1.1 Introduction ............................................ 3
1.2 Heterocycles as Framework of Biologically Active
Compounds ............................................... 4
1.3 Fine-Tuning the Physicochemical Properties with
Heterocycles ............................................ 6
1.4 Heterocycles as Prodrugs ................................ 6
1.5 Heterocycles as Peptidomimetics ......................... 7
1.6 Heterocycles as Isosteric Replacement of Functional
Groups .................................................. 8
1.7 Heterocycles as Isosteric Replacement of Alicyclic
Rings .................................................. 11
1.8 Heterocycles as Isosteric Replacement of other
Heterocyclic Rings ..................................... 13
References .................................................. 16
Part I Neurological Disorders ................................. 21
2 Tropane-Based Alkaloids as Muscarinic Antagonists for the
Treatment of Asthma, Obstructive Pulmonary Disease, and
Motion Sickness ............................................. 23
Michael L. Schulte and Craig W. Lindsley
2.1 Introduction ........................................... 23
2.2 History ................................................ 23
2.3 Synthesis .............................................. 25
2.4 Mode of Action ......................................... 29
2.5 Structure-Activity Relationships ....................... 32
References .................................................. 34
3 Morphinone-Based Opioid Receptor Agonist Analgesics ......... 37
Stephanie M. Ng
3.1 Introduction ........................................... 37
3.2 History ................................................ 37
3.3 Synthesis .............................................. 40
3.4 Mode of Action ......................................... 43
3.5 Structure-Activity Relationship ........................ 44
References .................................................. 48
4 Barbituric Acid-Based CABA(A) Receptor Modulators for the
Treatment of Sleep Disorder and Epilepsy and as
Anesthetics ................................................. 51
Ingo Janser and Romy Janser
4.1 Introduction ........................................... 51
4.2 History ................................................ 52
4.2.1 Barbiturates in the Treatment of Sleep
Disorders ....................................... 55
4.2.2 Barbiturates in the Treatment of Epilepsy ....... 55
4.2.3 Barbiturates as Anesthetics ..................... 56
4.3 Synthesis .............................................. 57
4.4 Mode of Action ......................................... 60
4.5 Structure-Activity Relationship ........................ 62
4.5.1 5,5-Disubstitution .............................. 62
4.5.2 Substitution at the Nitrogens ................... 63
References .................................................. 63
5 Phenothiazine-Based Dopamine D2 Antagonists for the
Treatment of Schizophrenia .................................. 65
Cristiana A. Zaharia
5.1 Introduction ........................................... 65
5.2 History ................................................ 65
5.3 Synthesis .............................................. 70
5.4 Mode of Action ......................................... 72
5.5 Structure-Activity Relationships ....................... 76
References .................................................. 77
6 Arylpiperazine-Based 5-НТ-1A Receptor Partial Agonists and
5-НT2A Antagonists for the Treatment of Autism,
Depression, Anxiety, Psychosis, and Schizophrenia ........... 81
Irini Akritopoulou-Zanze
6.1 Introduction ........................................... 81
6.2 History ................................................ 81
6.3 Synthesis .............................................. 85
6.4 Mode of Action ......................................... 88
6.5 Structure-Activity Relationship ........................ 89
References .................................................. 96
7 Arylpiperidine-Based Dopamine D2 Antagonists/5-HT2A
Antagonists for the Treatment of Autism, Depression,
Schizophrenia, and Bipolar Disorder ......................... 99
Ying Wang
7.1 Introduction ........................................... 99
7.2 History ................................................ 99
7.3 Synthesis ............................................. 106
7.4 Mode of Action ........................................ 109
7.5 Structure-Activity Relationship ....................... 111
References ................................................. 113
8 Dibenzazepine-Based Sodium Channel Blockers for the
Treatment of Neuropathic Pain .............................. 115
Derek W. Nelson
8.1 Introduction .......................................... 115
8.2 History ............................................... 115
8.3 Synthesis ............................................. 119
8.4 Mode of Action ........................................ 124
8.5 Structure-Activity Relationships ...................... 128
References ................................................. 130
Part II Cardiovascular Diseases .............................. 135
9 Dihydropyridine-Based Calcium Channel Blockers for the
Treatment of Angina Pectoris and Hypertension .............. 137
Milan Bruncko
9.1 Introduction .......................................... 137
9.2 History ............................................... 139
9.3 Synthesis ............................................. 141
9.4 Mode of Action ........................................ 144
9.5 Structure-Activity Relationship ....................... 148
References ................................................. 149
10 Tetrazole-Based Angiotensin II Type 1 (ATn) Antagonists
for the Treatment of Heart Failure and Congestive
Hypertension ............................................... 153
Edward C. Lawson, Brian C. Shook, and James C. Lanter
10.1 Introduction .......................................... 153
10.2 History ............................................... 154
10.3 Synthesis ............................................. 157
10.4 Mode of Action ........................................ 159
10.5 Structure-Activity Relationship ....................... 161
References ................................................. 163
11 Thiazide-Based Diuretics for the Treatment of
Hypertension and Genitourinary Disorders ................... 169
Jürgen Dinges
11.1 Introduction .......................................... 169
11.2 History ............................................... 169
11.3 Synthesis ............................................. 174
11.4 Mode of Action ........................................ 177
11.5 Structure - Activity Relationship ..................... 179
References ................................................. 180
12 Tetrahydropyranone-Based HMC-CoA Reductase Inhibitors for
the Treatment of Arterial Hypercholesterolemia ............. 183
Hongyu Zhao
12.1 Introduction .......................................... 183
12.2 History ............................................... 183
12.3 Synthesis ............................................. 188
12.4 Mode of Action ........................................ 191
12.5 Structure-Activity Relationship ....................... 192
12.5.1 The Hydrophilic Dihydroxypentanoic Acid
Portion ........................................ 192
12.5.2 The SAR of Natural Statins ..................... 192
12.5.3 SAR of Synthetic Statins ....................... 195
12.5.4 Liver-Selective HMGCoA Inhibitors .............. 197
12.5.5 X-Ray Crystal Structures ....................... 197
References ................................................. 198
Part III Infectious Diseases ................................. 201
13 Adenine-Based Reverse Transcriptase Inhibitors as
Anti-HIV Agents ............................................ 203
Alastair Donald
13.1 Introduction .......................................... 203
13.2 History ............................................... 203
13.3 Synthesis ............................................. 209
13.4 Mode of Action ........................................ 212
13.5 Structure-Activity Relationship ....................... 212
References ................................................. 214
14 Cuanine-Based Nucleoside Analogs as Antiviral Agents ....... 217
Maurizio Franzini
14.1 Introduction .......................................... 217
14.2 History ............................................... 219
14.3 Synthesis ............................................. 221
14.4 Mode of Action ........................................ 227
14.5 Structure-Activity Relationship ....................... 229
References ................................................. 232
15 Penicillin and Cephalosporin Antibiotics ................... 237
Michael Z. Hoemann
15.1 Introduction .......................................... 237
15.2 History ............................................... 237
15.3 Synthesis ............................................. 239
15.3.1 Total Syntheses ................................ 239
15.3.2 Core Modifications ............................. 243
15.4 Mode of Action ........................................ 248
15.5 Structure-Activity Relationships ...................... 250
References ................................................. 251
Part IV Oncology ............................................. 255
16 Pyrimidine-Based Kinase Inhibitors in Cancer Chemotherapy .. 257
Robert Mah
16.1 Introduction .......................................... 257
16.2 History ............................................... 257
16.3 Synthesis ............................................. 261
16.4 Mode of Action ........................................ 264
16.5 Structure-Activity Relationship ....................... 266
References ................................................. 269
17 Benzyl Triazole-Based Aromatase Inhibitors for the
Treatment of Breast Cancer ................................. 275
Dawn George and Stacy Van Epps
17.1 Introduction .......................................... 275
17.2 History ............................................... 275
17.3 Synthesis ............................................. 277
17.4 Mode of Action ........................................ 281
17.5 Structure-Activity Relationship ....................... 282
References ................................................. 286
Part V Inflammation and Gastrointestinal Diseases ............ 289
18 Acetonide-Based Glucocorticoids for the Treatment of
Asthma, Skin Inflammation, and Diseases of the Eye ......... 291
Kevin P. Cusack, Vikram G. Kalthod, Rajarathnam E. Reddy,
and Sanjay R. Chemburkar
18.1 Introduction .......................................... 291
18.2 History ............................................... 293
18.3 Synthesis ............................................. 297
18.4 Mode of Action ........................................ 304
18.4.1 Asthma ......................................... 306
18.4.2 Skin Inflammation .............................. 307
18.4.3 Eye Disease .................................... 307
18.5 Structure-Activity Relationship ....................... 308
References ................................................. 311
19 Benzimidazole-Based H+/K+-ATPase Inhibitors for the
Treatment of Gastroesophageal Reflux Disease ............... 313
Steve Swann
19.1 Introduction .......................................... 313
19.2 History ............................................... 313
19.3 Synthesis ............................................. 316
19.4 Mode of Action ........................................ 319
19.5 Structure-Activity Relationships ...................... 320
References ................................................. 324
Part VI Metabolic Diseases ................................... 327
20 Thiazolidinedione-Based Insulin Sensitizers:PPAR-γ
Agonists for the Treatment of Type 2 Diabetes .............. 329
Steven Richards
20.1 Introduction .......................................... 329
20.2 History ............................................... 329
20.3 Synthesis ............................................. 337
20.4 Mode of Action ........................................ 343
20.5 Structure-Activity Relationship ....................... 344
References ................................................. 345
Index ...................................................... 349
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