Integration of pharmaceutical discovery and development: case histories
Gespeichert in:
| Weitere Verfasser: | |
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| Format: | Buch |
| Sprache: | English |
| Veröffentlicht: |
New York [u.a.]
Plenum Press
1998
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| Schriftenreihe: | Pharmaceutical biotechnology
11 |
| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | XXIX, 607 S. Ill., graph. Darst. |
| ISBN: | 0306457431 |
Internformat
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| 245 | 1 | 0 | |a Integration of pharmaceutical discovery and development |b case histories |c ed. by Ronald T. Borchardt ... |
| 264 | 1 | |a New York [u.a.] |b Plenum Press |c 1998 | |
| 300 | |a XXIX, 607 S. |b Ill., graph. Darst. | ||
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| 490 | 0 | |a Pharmaceutical biotechnology |v 11 | |
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| 700 | 1 | |a Borchardt, Ronald T. |4 edt | |
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| adam_text | xvi Contents
2.3. The Search for Tetrazole Replacements 33
2.4. Synthetic Availability of Biphenyltetrazoles 39
3. An Active Metabolite of Losartan 44
3.1. Identification of EXP3174 44
3.2. Should We Develop EXP3174? 45
3.3. The Search for a Superior EXP3174 Analogue 45
4. Early Evaluation of Losartan s Activity in Humans 47
5. Selective versus Balanced Angiotensin II Receptor Antagonists 48
6. Conclusion 51
References 52
Chapter 4
Development of an Orally Active Tripeptide Arginal Thrombin Inhibitor
Robert T. Shuman and Paul D. Gesellchen
1. Introduction 57
2. Identification of Lead Compounds 60
2.1. In Vitro Structure-Activity Relationships 61
2.2. In Vivo Structure-Activity Relationships 64
3. Development of Parenteral Clinical Candidate 69
3.1. Development of Licensed Compound (Efegatran) 69
3.2. Summary of Clinical Data on Efegatran 70
4. Development of an Oral Candidate 70
4.1. In Vivo Oral Bioavailability 71
4.2. Oral Dosing in Efficacy Models 73
4.3. Pharmacokinetics of Oral Candidate 73
4.4. Clinical Data for Oral Candidate 75
5. Conclusion 77
References 78
Chapter 5
Discovery and Development of an Endothelin A Receptor-Selective
Antagonist PD 156707
Annette M. Doherty and Andrew C. G. Uprichard
1. Introduction 81
2. Discovery of PD 156707: Medicinal Chemistry, Pharmacology,
and Pharmacokinetics 84
Contents xvii
2.1. Identification of Lead Structures 84
2.2. Structure-Activity Relationships 86
2.3. Pharmacokinetics/Selection 87
2.4. Chemistry/Chemical Development 89
2.5. Biological Evaluation of PD 156707 90
2.6. Metabolism 92
2.7. Assay Development 93
3. Efficacy Studies: Which Disease States? 96
3.1. Hypertension 96
3.2. Heart Failure 99
3.3. Pulmonary Hypertension 100
3.4. Stroke 103
4. Future Plans 103
5. Summary 105
References 105
Chapter 6
Endothelin Receptor Antagonists
John D. Elliott, Eliot H. Ohlstein, Catherine E. Peishoff, Harma M. Ellens,
and M. Amparo Lago
1. Introduction 113
2. Rational Design of SB 209670 115
3. Pharmacological, Drug Metabolism, and Pharmacokinetic
Characterization of SB 209670 121
4. Selection of the Orally Bioavailable Candidate SB 217242 121
5. Conclusion 127
References 127
Chapter 7
LHRH Antagonists
Fortuna Haviv, Eugene N. Bush, Judith Knittle, and Jonathan Greer
1. Mechanism of Action of LHRH Agonists and Antagonists 131
2. Structural Differences of LHRH Agonists and Antagonists 133
2.1. Reduction of Size of LHRH Analogues 135
xviii Contents
2.2. Enzymatic Stability of LHRH Analogues and Effect of N-methyl
Substitution on Enzymatic Stability of LHRH Agonists 136
2.3. Effect of iV-methyl Substitution on Water Solubility of LHRH
Antagonists. Discovery of A-75998 137
3. Biological Testing Strategy 137
3.1. In Vitro Testing of A-75998: Receptor Binding, Inhibition of LH
Release, and Histamine Release 138
3.2. In Vivo Studies of A-75998 in Rat, Dog, and Monkey 138
3.3. Pharmacokinetics of A-75998 in Rat, Dog, and Monkey 140
4. Aggregation and Formulation of A-75998 141
5. LHRH Antagonists in Clinical Evaluation 144
5.1. Clinical Study of A-75998 144
5.2. Current LHRH Antagonists in Clinical Studies 144
6. Summary 146
References 146
Chapter 8
LHRH Agonists
Kenneth W. Funk, Jonathan Greer, and Akwete L. Adjei
1. Introduction 151
1.1. Background 152
1.2. Drug Candidate Selection 153
2. Physical Chemistry and Chemical Characterization 157
2.1. Bulk Drug Synthesis 158
2.2. Manufacturing Controls 160
2.3. Physical Characteristics and Methods 161
2.4. Chemical Characterization and Methods 163
2.5. Moisture and Acetic Acid 163
2.6. Amino Acid Analysis 164
3. Formulation Chemistry of Leuprolide Acetate 165
3.1. In Vitro Studies 165
3.2. In Vivo Studies 166
4. Clinical Development 169
4.1. Standards and Controls 169
4.2. Physical and Chemical Characterization 171
4.3. Pathology and Toxicology 174
4.4. Clinical Pharmacokinetics and Pharmacodynamics 177
5. Conclusions 178
References 179
Contents xix
Chapter 9
Discovery and Development of Somatostatin Agonists
Peter Marbach, Wilfried Bauer, David Bodmer, Ulrich Briner, Christian Bruns,
Andrea Kay, Ioana Lancranjan, Janos Pless, Friedrich Raulf, Rodney Robison,
John Sharkey, Thomas Soranno, Barbara Stolz, Peter Vit, and Gisbert
Weckbecker
1. Introduction 183
2. Somatostatin Receptors 184
2.1. Heterogeneity of Somatostatin Receptors 184
2.2. The Somatostatin Receptor Gene Family 184
2.3. Tissue Distribution 185
2.4. Pharmacology 186
3. Discovery and Development of Sandostatin® 186
3.1. Synthesis of Octreotide 189
3.2. Pharmacodynamic Tests 190
3.3. Pharmacokinetic Studies 191
3.4. Toxicology 191
3.5. Clinical Development 192
4. Development of Sandostatin® LAR® 193
4.1. Manufacture 194
4.2. Preclinical Studies 194
4.3. Clinical Studies 195
5. Oncolar™: Technical Development of a New LAR Formulation
of Octreotide 196
5.1. Manufacture 196
5.2. Preclinical Studies 196
6. Antiproliferative Effects of Single-Agent Octreotide 197
6.1. Mechanism of Antiproliferative Action 198
6.2. Route of Administration and Plasma Levels 199
6.3. Octreotide as a Potentiator of Standard Anticancer Regimens .... 199
7. Development of Octreotide for Oncological Uses beyond the Control
of Disease-Related Symptoms in GEP Tumors 201
7.1. Somatostatin Receptor Binding and Growth Factor
Suppression 201
7.2. Clinical Trials 202
8. Radiolabeled Octreotide Analogues 202
8.1. Imaging of Tumors with OctreoScan® 203
8.2. Tumor Radiotherapy with SMT 487 203
9. Summary and Outlook 204
References 205
xx Contents
Chapter 10
Factors Impacting the Delivery of Therapeutic Levels of Pyrone-Based HIV
Protease Inhibitors
Guy E. Padbury, Gail L. Zipp, Francis J. Schwende, Zhiyang Zhao, Kenneth A.
Koeplinger, Kong Teck Chong, Thomas J. Raub, and Suvit Thaisrivongs
1. Introduction 211
1.1. HIV Protease as a Therapeutic Target 211
1.2. Pyrone-Based Inhibitors 213
1.3. Factors that Affect Drug Delivery 215
1.4. Life in a Perfect World 215
2. Efficacy 216
2.1. Effect/Importance of Protein Binding 216
2.2. Clinical Targets 219
3. Pharmacokinetics 220
3.1. Total versus Unbound Intrinsic Clearance 220
3.2. Factors Affecting Clearance 221
3.3. Absolute Oral Bioavailability versus Systemic Exposure 224
4. Life in the Real World 225
4.1. Selection of a Viable Chemical Template 225
4.2. Identification of a Final Clinical Candidate 227
References 229
Chapter 11
The Integration of Medicinal Chemistry, Drug Metabolism, and
Pharmaceutical Research and Development in Drug Discovery and
Development: The Story of Crixivan®, an HIV Protease Inhibitor
Jiunn H. Lin, Drazen Ostovic, and Joseph P. Vacca
1. Introduction 233
2. Discovery of L-735,524 (Crixivan®) 234
3. Improvement of Solubility 238
4. Physicochemical Properties of MK-639 (Indinavir) 241
5. pH-Dependent Oral Absorption 246
6. In Vitro/In Vivo Metabolism 248
7. Backup Compounds 249
8. Conclusion 252
References 254
Contents xxi
Chapter 12
De Novo Design and Discovery of Cyclic HIV Protease Inhibitors Capable
of Displacing the Active-Site Structural Water Molecule
George V De Lucca, Prabhakar K. Jadhav, Robert E. Waltermire, Bruce J.
Aungst, Susan Erickson-Viitanen, and Patrick Y. S. Lam
1. Introduction 257
2. Initiation of Program at DMPC 258
3. Design of Cyclic Ureas 259
3.1. De Novo Design 259
3.2. Confirmation of Design 262
3.3. Molecular Recognition 265
4. First Clinical Candidate DMP 323 266
4.1. Discovery and Optimization 266
4.2. Chemistry and Process Development 267
4.3. Clinical Study 270
5. Second Clinical Candidate DMP 450 270
5.1. Discovery and Optimization 270
5.2. Safety and Pharmacokinetics 271
5.3. Chemistry and Process Development 272
5.4. Clinical Study 273
6. Future Cyclic Ureas 274
6.1. Potency 275
6.2. Resistance Profile 276
6.3. Pharmacokinetics 278
6.4. Design and Physicochemical Properties 280
7. Conclusion 280
References 281
Chapter 13
Discovery and Development of the BHAP Nonnucleoside Reverse
Transcriptase Inhibitor Delavirdine Mesylate
Wade J. Adams, Paul A. Aristqff, Richard K. Jensen, Walter Morozowich,
Donna L. Romero, William C. Schinzer, W. Gary Tarpley,
and Richard C. Thomas
1. Introduction, Goals, and Strategy 285
2. Discovery of Initial Lead (PNU-80493E) 287
xxii Contents
3. Selection of First-Generation Candidate (PNU-87201) 288
4. Development of PNU-87201E (Atevirdine Mesylate) 292
5. Goals for Second-Generation Candidate 292
6. Selection Process 293
7. Water-Soluble Compounds 294
8. Development of PNU-90152T (Delavirdine Mesylate) 300
8.1. Pharmacology 300
8.2. Formulation/Salt Selection/Crystal Form 301
8.3. Absorption, Distribution, Metabolism, and Excretion 305
8.4. Safety/Tbxicokinetics 308
8.5. Clinical Summary 309
9. Conclusions 310
References 310
Chapter 14
Famciclovir: Discovery and Development of a Novel Antiherpesvirus Agent
Richard L. Jarvest, David Sutton, and R. Anthony Vere Hodge
1. Introduction 313
1.1. Identification of Penciclovir as an Antiherpesvirus Agent 314
1.2. Antiviral Activity and Spectrum of Activity 315
1.3. Mechanism of Action 316
1.4. Oral Bioavailability 321
2. Prodrug Forms of Penciclovir 321
2.1. Strategy and Evaluation of Oral Bioavailability 321
2.2. Evaluation of Metabolic Conversion in Human Body Fluids
and Tissues 326
2.3. Selection of Preferred Oral Candidate: Famciclovir 327
2.4. Other Routes of Administration 327
3. Preclinical Evaluation of Famciclovir 329
3.1. Animal Models of Infection 329
3.2. Chirality of Metabolic Products from Famciclovir 330
3.3. Identification of Enzymatic Oxidation in Humans 331
4. Clinical Evaluation 331
4.1. Metabolism and Pharmacokinetics 331
4.2. Efficacy 333
5. Conclusion 337
References 338
i Contents xxiii
Chapter 15
The Use of Esters as Prodrugs for Oral Delivery of 3-Lactam Antibiotics
Linda Mizen and George Burton
1. Introduction 345
2. Chemical Overview 347
3. Animal Bioavailability Studies and Selection 350
3.1. Penicillins, Penems, Trinem 351
3.2. Cephalosporins 353
4. Hydrolysis Rates and Physicochemical Properties 357
4.1. Hydrolysis by Liver 357
4.2. Hydrolysis by Small Intestine 358
4.3. Hydrolysis by Blood 358
4.4. Physicochemical Properties 360
5. Dosing Vehicles and Formulations 361
6. Summary and Conclusions 361
References 362
Chapter 16
Hematoregulators: A Case History of a Novel Hematoregulatory Peptide,
SK F 107647
Pradip K. Bhatnagar, William F. Huffman, Andrew G. King, Dagfinn L0vhaug,
Louis M. Pelus, William M. Potts, Philip L Smith
1. Introduction 367
2. Hematopoiesis, Endogenous Regulators, and Host Defense
Mechanism 368
3. Unmet Needs 369
4. Nonproteinaceous Hematoregulators 371
4.1. Polymeric Carbohydrate: Betafectin 371
4.2. Low-Molecular-Weight Hematoregulators 371
5. SK F 107647 and Analogues 375
5.1. Structure-Activity Relationships of SK F 107647 376
5.2. Mechanism of Action 379
5.3. Colony Stimulating Activity Induction Assay 379
5.4. Hematopoietic Synergistic Factor Assay 379
5.5. Preclinical Studies 380
I 6. Conclusions 383
1 References 384
3
xxiv Contents
Chapter 17
Discovery and Development of GG745, a Potent Inhibitor of Both Isozymes
of 5a-Reductase
Stephen V. Frye, H. Neal Bramson, David J. Hermann, Frank W. Lee,
Achintya K. Sinhababu, and Gaochao Tian
1. Introduction 393
1.1. 5a-Reductases 393
1.2. Pathophysiology of DHT 397
1.3. Finasteride: Clinical Effects of a Type 2-Selective 5a-Reductase
Inhibitor 398
1.4. Potential Utility of a Dual 5a-Reductase Inhibitor 399
2. Enzymology of 5a-Reductases 399
2.1. Time Dependence of Inhibition by A1 4-Azasteroids 399
2.2. Modeling of the Clinical Effect of Finasteride 404
3. Discovery of Dual 5a-Reductase Inhibitors: 6-Azasteroids 405
3.1. Medicinal Chemistry 405
3.2. Pharmacokinetic Studies: In Vivo and in Vitro Correlations 408
4. Discovery of GG745 410
5. Initial Clinical Studies with GG745 413
5.1. Interspecies Scaling/Dose Selection 413
5.2. Pharmacokinetic and Pharmacodynamic Results in Man 414
References 417
Chapter 18
Discovery of a Potent and Selective ot1A Antagonist: Utilization of a Rapid
Screening Method to Obtain Pharmacokinetic Parameters
Kimberly K. Adkison, Kathy A. Halm, Joel E. Shaffer, David Drewry,
Achintya K. Sinhababu, and Judd Berman
1. Introduction 423
1.1. Benign Prostatic Hyperplasia 423
1.2. Therapeutic Use of a1A-Selective Antagonists 424
1.3. Project Goal 425
2. Research Strategy 425
2.1. Compound Progression and Critical Path 425
2.2. Discovery of a ]A-SelectiveOxazole-Containing Antagonists .... 426
: Contents xxv
3. Pharmacokinetic/Pharmacodynamic Strategy 433
3.1. In Vitro Metabolism Screening Prior to Pharmacokinetic
Studies 433
3.2. Improved Pharmacokinetic Throughput: Mixture Dosing
Coupled with LC/MS Analysis 434
3.3. Pharmacokinetic Evaluation of Other Leads 439
3.4. Pharmacodynamics of the Lead Compound 440
4. Advancement of Compound 18 to Exploratory Development 442
References 442
Chapter 19
Discovery of Bioavailable Inhibitors of Secretory Phospholipase A2
Steven G. Blanchard, Robert C. Andrews, Peter J. Brown, Liang-Shang L. Gan,
Frank W. Lee, Achintya K. Sinhababu, and Thomas N. Wheeler
1. Introduction 445
1.1. Therapeutic Target 445
1.2. Program Objective 446
2. In Vitro Identification of Active-Site Inhibitors of sPLA2 446
2.1. Dual Substrate Strategy for Inhibitor Discovery 446
2.2. In Vitro Profile of Substrate Analogue PLA2 Inhibitors 447
3. In Vivo Anti-inflammatory Activity of Initial Candidates 448
3.1. Choice of Animal Model 448
3.2. In Vivo Activity Is Dependent on Formulation of the Test
Compound 449
3.3. Activity in the Rat Carrageenan Paw Edema Model 450
4. Pharmacokinetic and Metabolic Fate of Candidate Inhibitors 452
4.1. Plasma Levels and Metabolic Profiles after i.v. and p.o. Dosing ... 452
4.2. In Vitro Studies 453
4.3. Conclusions Based on Metabolism Studies 457
5. Preparation of Inhibitors Designed to Address the Observed Metabolic
Instability 458
5.1. Synthesis and in Vitro Evaluation of Inhibitory Activity 458
5.2. Evaluation of in Vitro Stability 460
5.3. Pharmacokinetic Studies 460
5.4. In Vivo Activity of Inhibitors with Improved Metabolism
and Pharmacokinetics 460
l
xxvi Contents
6. Summary and Conclusions 461
References 462
Chapter 20
The Anxieties of Drag Discovery and Development:
CCK-B Receptor Antagonists
Franco Lombardo, Steven M. Winter, Larry Tremaine, and John A. Lowe III
1. Introduction 465
2. Chemistry 466
3. Initial Drug Metabolism Studies 468
4. Formulation Studies 471
5. A New Analogue with Improved Aqueous Solubility: CP-310,713 .... 476
6. Lessons Learned 477
References 478
Chapter 21
CI-1015: An Orally Active CCK-B Receptor Antagonist with an Improved
Pharmacokinetic Profile
Bharat K. Trivedi and Joanna P. Hinton
1. Introduction 481
1.1. First-Generation CCK-B Antagonists 482
1.2. CI-988 Pharmacokinetic Retrospective 483
1.3. Objectives of the Discovery Team 488
2. Discovery of CI-1015 488
2.1. Design Strategy 488
2.2. Structure-Activity Relationship Study 488
3. Preclinical Characterization of Backup Candidates 494
3.1. In Vitro and in Vivo Comparison 494
3.2. Pharmacokinetic Evaluations in Rat 494
3.3. Brain Penetration Studies 498
3.4. Evaluation of Potential for Gastric Acid Secretion 499
3.5. Pharmacokinetic Evaluation in Monkey 500
4. Conclusion 500
References 503
Contents xxvii
Chapter 22
Orally Active Nonpeptide CCK-A Agonists
Elizabeth E. Sugg, Lawrence Birkemo, Liang-Shang L. Gan,
and Timothy K. Tippin
1. Introduction 507
2. In Vivo Profile of GW7854 508
3. Pharmaceutical Studies with GW7854 510
3.1. Batch Variation 510
3.2. Dosing Vehicle 510
4. Pharmacology Studies 510
4.1. The Mouse Gallbladder Emptying Assay 510
4.2. Alternate Species 511
4.3. The Conditioned Feeder Rat Model 511
5. Pharmacokinetic Profile of GW7854 511
6. The Caco-2 Model for Intestinal Absorption 512
6.1. Correlation with Rat Intestinal Absorption 513
6.2. Structure-Transport Relationships 513
7. Bioavailability versus Bioactivity 516
8. Oral versus Intraduodenal Dosing 521
9. Discussion 521
10. Clinical Implications 522
References 522
Chapter 23
Orally Active Growth Hormone Secretagogues
Arthur A. Patchett, Roy G. Smith, and Matthew J. Wyvratt
1. Introduction 525
2. Discovery of GHRP-6 Mimics: Benzolactam L-692,429 527
2.1. Clinical Studies with L-692,429 528
2.2. Structure-Activity-Bioavailability Relationships
for the Benzolactams 529
3. New Structural Leads 534
3.1. Privileged Structure Screening 534
3.2. Discovery of MK-0677 536
4. Mechanism of Action of GH Secretagogues 544
j 4.1. Biochemistry 544
xxviii Contents
4.2. Characterization of the GH Secretagogue Receptor (GHS-R) 545
4.3. Cloning the GH Secretagogue Receptor 546
4.4. GH Secretagogue Receptor and GH Pulsatility 546
5. Conclusion 547
References 549
Chapter 24
Dorzolamide, a 40-Year Wait: From an Oral to a Topical Carbonic
Anhydrase Inhibitor for the Treatment of Glaucoma
Gerald S. Ponticello, Michael F. Sugrue, Bernard Plazonnet, and Genevieve
Durand-Cavagna
1. Introduction 555
2. Benzothiazoles 557
3. Benzothiophenes 558
4. Thienothiopyrans 559
5. Dorzolamide 560
6. Pharmacology 563
6.1. In Vitro 563
6.2. In Vivo 564
7. Pharmaceutical Research and Development Studies 566
8. Safety Assessment Studies 567
9. Summary 571
References 572
Chapter 25
Discovery and Development of Novel Melanogenic Drugs:
Melanotan-I and -II
Mac E. Hadley, Victor J. Hruby, James Blanchard, Robert T. Dorr, Norman
Levine, Brenda V. Dawson, Fahad Al-Obeidi, and Tomi K. Sawyer
1. Introduction 575
2. The Melanocortin Peptides and Receptors 576
2.1. Melanocortin Peptides 576
2.2. Melanocortin Receptors 577
3. Discovery of the MT-I and MT-II as MSH Superagonists 579
3.1. Structure-Activity Studies of a-MSH 579
3.2. Design and Chemistry of MT-I and MT-II 580
Contents xxix
3.3. In Vitro and in Vivo Pharmacology of MT-I and MT-II 582
4. Development of MT-I and MT-II as Novel Melanogenic Drugs 583
4.1. Stability, Pharmacokinetic, and Toxicological Studies 583
4.2. Drug Delivery and Clinical Studies 585
5. Summary and Future Directions 590
References 591
Index 597
I
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| any_adam_object | 1 |
| author2 | Borchardt, Ronald T. |
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| author_facet | Borchardt, Ronald T. |
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| ctrlnum | (OCoLC)245723263 (DE-599)BVBBV023745011 |
| dewey-full | 615.19 |
| dewey-hundreds | 600 - Technology (Applied sciences) |
| dewey-ones | 615 - Pharmacology and therapeutics |
| dewey-raw | 615.19 |
| dewey-search | 615.19 |
| dewey-sort | 3615.19 |
| dewey-tens | 610 - Medicine and health |
| discipline | Chemie / Pharmazie Medizin |
| format | Book |
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| id | DE-604.BV023745011 |
| illustrated | Illustrated |
| indexdate | 2024-07-09T21:33:51Z |
| institution | BVB |
| isbn | 0306457431 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-017294086 |
| oclc_num | 245723263 |
| open_access_boolean | |
| owner | DE-526 |
| owner_facet | DE-526 |
| physical | XXIX, 607 S. Ill., graph. Darst. |
| publishDate | 1998 |
| publishDateSearch | 1998 |
| publishDateSort | 1998 |
| publisher | Plenum Press |
| record_format | marc |
| series2 | Pharmaceutical biotechnology |
| spelling | Integration of pharmaceutical discovery and development case histories ed. by Ronald T. Borchardt ... New York [u.a.] Plenum Press 1998 XXIX, 607 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Pharmaceutical biotechnology 11 Arzneimittelentwicklung (DE-588)4143176-5 gnd rswk-swf Arzneimittelentwicklung (DE-588)4143176-5 s DE-604 Borchardt, Ronald T. edt HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=017294086&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Integration of pharmaceutical discovery and development case histories Arzneimittelentwicklung (DE-588)4143176-5 gnd |
| subject_GND | (DE-588)4143176-5 |
| title | Integration of pharmaceutical discovery and development case histories |
| title_auth | Integration of pharmaceutical discovery and development case histories |
| title_exact_search | Integration of pharmaceutical discovery and development case histories |
| title_full | Integration of pharmaceutical discovery and development case histories ed. by Ronald T. Borchardt ... |
| title_fullStr | Integration of pharmaceutical discovery and development case histories ed. by Ronald T. Borchardt ... |
| title_full_unstemmed | Integration of pharmaceutical discovery and development case histories ed. by Ronald T. Borchardt ... |
| title_short | Integration of pharmaceutical discovery and development |
| title_sort | integration of pharmaceutical discovery and development case histories |
| title_sub | case histories |
| topic | Arzneimittelentwicklung (DE-588)4143176-5 gnd |
| topic_facet | Arzneimittelentwicklung |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=017294086&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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