Edited by
`Janos Fischer and
`C. Robin Gane/fin
`
`Analogue-based Drug
`Discovery II
`
`MPI EXHIBIT 1033 PAGE 1
`
`

`

`Edited by
`Janos Fischer and C. Robin Gane/Jin
`
`Analogue-based Drug Discovery II
`
`@
`
`WILEY(cid:173)
`YCH
`WILEY-VCH Verlag GmbH & Co. KGaA
`
`MPI EXHIBIT 1033 PAGE 2
`
`

`

`The Editors
`
`Prof. Dr. Janos Fischer
`Richter Pie
`Cyomroi u L 30
`1103 Budapest
`Hungary
`
`Prof. Dr. C. Robin Conelli,,
`University College London
`Department of Chemistry
`20 Gordon StrccL
`London WCIH OAJ
`United Kingdom
`
`Supported by
`
`The International Union of Pure and AppUcd
`Chemistry (IUPAC)
`Chemistry and Human Health Devision
`PO Box 13757
`Rcsca,ch Triangle Park, NC 27709-3757
`USA
`
`Ail books published by Wilcy-VCH arc carefully
`produced. Nevertheless. authors, editors, and
`publisher do not warrant the information contained
`in these books, including this book, to be free of
`errors . Rc,dcrs arc •dvisc<I Lo keep in nund that
`sutcments, data, illustration.~. procedural details or
`other items may inadvcrtcndy be inaccurate.
`
`1
`
`Libr::ary of Ce>ngrocc C::ard N o.: :ippli~ for
`
`British Library Cataloguing-in-Publication Data
`A catalogue record for this book is available from the
`British Library.
`
`Bibliographic information publi.shed by
`the Deutsche N ationalbibliothek
`The DcuL~chc Nationalbibliothck lisL~ this
`publication in the DcuL~c Nationalbibliogr:ific;
`detailed bibliog-raphic data arc available on U1e
`lnLcrnct >l hLLp://dnb.d-nb.dc.
`
`© 2010 WILEY-VCJ-1 Verlag GmbH & Co. KGaA,
`Wcinheim
`
`All righL~ reserved (including those ofLrarnlation into
`other languages). No part of this book may be
`reproduced in any form - by photoprinting,
`tnicroftlm, or any other means - nor Lransmittcd or
`translated into a machine language without wriucn
`permission from U1e publishers. Registered names,
`tra.dcma.rks, etc. used in Lhis book, even when nol
`specifically marked as such, arc not to be considered
`unprotected by law.
`
`Cover Design Ad:1m D e:~ign, Wcinhcim
`Typesetting Thomson Digital, Noida, India
`Printing and Binding SLrauss GmbH, Morlcnbach
`
`Printed in u1c Federal Republic of Germany
`Printed on acid-free paper
`
`ISBN: 978-3-527-325~9-8
`
`MPI EXHIBIT 1033 PAGE 3
`
`

`

`Contents
`
`Preface XV
`Introduction XVII
`Abbreviations XXI
`
`Part I
`
`General Aspects 1
`
`Optimizing Drug Therapy by Analogues 3
`Janos Fischer, C. Robin Canel/in, John Proudfoot, and Erika M. Alapi
`Introduction 3
`Pharmacodynamic Characteristics 4
`Potency 4
`Improving the Ratio of Main Activity and Adverse Effects 5
`Improving Selectivity Through Receptor Subtypes 6
`Improving Selectivity Through Unrelated Receptors 7
`Improving Selectivity by Tissue Distribution 7
`Improving Selectivity of Nonreceptor-Mediated Effects 10
`Improving the Physicochemical Properties with Analogues 10
`Analogues to Reduce the Resistance to Anti-Infective Drugs 11
`Antibiotics 11
`Antifungal Drugs 12
`Antiviral Drugs 12
`Analogue Research in Resistance to Drug Therapies in Cancer
`Treatment 15
`Pharmacokinetic Characteristics 15
`Improving Oral Bioavailability 15
`Improving Absorption 16
`Improving Metabolic Stability 16
`Drugs with a Long Duration of Action 17
`Ultrashort-Acting Drugs 18
`Decreasing Interindividual Pharm2cok:inetic Differences 20
`Decreasing Systemic Activity 21
`
`1.1
`1.2
`1.2.1
`1.2.2
`1.2.2.1
`1.2.2.2
`1.2.2.3
`1.2.2.4
`1.2.3
`1.2.4
`1.2.4.1
`1.2.4.2
`1.2.4.3
`1.2.5
`
`1.3
`1.3.1
`1.3.1.1
`1.3.1.2
`1.3.2
`1.3.3
`1.3.4
`1.3.5
`
`Analogue-based Drug Discovery JI. Edited by Janos Fischer and C. Robin Gancllin
`Copyright© 2010 WILEY-VCJ-1 Verlag Gmbl-1 & Co. KGaA, Weinheim
`ISBN: 978-3-527-32549-8
`
`MPI EXHIBIT 1033 PAGE 4
`
`

`

`VI I Contents
`
`1.4
`1.4.1
`1.4.2
`1.5
`
`2
`
`2.1
`2.2
`2.3
`2.3.1
`
`2.3.2
`2.3.3
`2.4
`2.5
`2.6
`2.7
`2.8
`2.9
`2.10
`
`3
`
`3.1
`3.2
`3.3
`3.4
`3.5
`3.6
`3.7
`
`4
`
`4.1
`4.2
`4.3
`4.4
`4.5
`4.6
`4.7
`
`Drug Interactions 22
`Decreasing Drug Interactions 22
`Increasing Drug Interactions 23
`Summary 23
`References 24
`
`Standalone Drugs 29
`Janos Fischer, C. Robin Canel/in, Arun Ganesan, and John Proudfoot
`Acetaminophen (Paracetamol) 30
`Acctylsalicylic Acid (Aspirin) 33
`Aripiprazole 35
`First Generation "Typical" Antipsychotic Drugs (Other Names:
`Neuroleptics, Conventional Antipsychotics) 36
`Second-Generation "Atypical" Antipsychotic Drugs 37
`A New Approach: Aripiprazole, a Dopamine Partial Agonist 38
`Bupropion 39
`Ezetimibe 42
`l.amotrigine 46
`Metformin 47
`Topiramate 49
`Valproate 51
`Summary 52
`References 53
`
`Application of Molecular Modeling in Analogue-Based
`Drug Discovery 61
`Gyorgy G. Ferenczy
`Introduction 61
`Cilazapril: An ACE Inhibitor 62
`Alorvastatin: A HMG-CoA Reductase Inhibitor 66
`PDE4 Inhibitors 70
`GPIIb/ I!Ia Antagonists 73
`HIV Protease Inhibitors 74
`Epilogue 79
`References 79
`
`Issues for the Patenting of Analogues 83
`Stephen C. Smith
`Introduction 83
`Patents: Some Fundamentals 84
`Patentability 85
`Important Elements of the International Patent System 86
`Priority 87
`Novelly 88
`Inventive Step: Nonobviousness 90
`
`MPI EXHIBIT 1033 PAGE 5
`
`

`

`Contents I VII
`
`4.8
`4.9
`4.10
`4.11
`4.12
`4.12.1
`4.12.2
`4.12.3
`4.12.4
`4.12.5
`4.12.6
`4.12.7
`4.12.8
`4.12.9
`4.12.10
`4.13
`
`Utility: lnduslTial Application 93
`Selection Inventions 93
`Enantiomers 94
`Prodrugs and Active Metabolites 95
`The Patenting Process from the Imentor's Standpoint 97
`Inventorship 98
`The Priority Patent Application 98
`Prior Ari Disclosure 98
`Patent Specification Review 99
`"Best Mode" of Carrying Out the Invention 99
`Foreign Patent Applications 99
`Patent Application Publication 100
`Patent Examination 100
`Opposition to Grant 101
`Patent Litigation 102
`Pitfalk for the Unw3.IY- Cr=ted Versus Published Patents,
`Scientific Publications 102
`References 105
`
`Part II
`
`Analogue Classes 107
`
`5
`
`5.1
`5.2
`
`5.3
`5.4
`5.5
`5.6
`5.7
`
`6
`
`6.1
`6.2
`6.2.1
`6.2.2
`6.2.3
`6.2.4
`6.3
`6.3.1
`6.3.2
`
`Dipeptidyl Peptidase IV Inhibitors for the Treatment
`ofType 2 Diabetes 109
`Jens-Uwe Peters and Patrizio Ma ttei
`Introduction 109
`In Vitro Assays and Animal Models for the Assessment
`ofDPP-IV Inhibitors 110
`Substrate-Based DPP-IV Inhibitors 110
`Sitagliptin and Analogues 119
`Xanthines and Analogues 122
`Pharmacological Comparison of DPP-IV Inhibitors 125
`Concluding Remarks 127
`References 128
`
`Phosphodiesterase S Inhibitors to Treat Erectile Dysfunction 135
`Nils Griebenow, Helmut Haning, and Erwin Bischoff
`Introduction 135
`Pharmacology of Phosphodiesterases 136
`The Phosphodiesterase Family 136
`Pharmacological Effects of cGMP 137
`PDES: Regulation, Activation, and SITucture 138
`PDES Inhibitors and Erectile Dysfunction 143
`Pyrimidinone PDES Inhibitors H7
`Xanlhines and cGMP Analogues 147
`PDES Inhibitors Incorporating the Purinone Nucleus 150
`
`MPI EXHIBIT 1033 PAGE 6
`
`

`

`VIII I Contents
`
`6.3.2.1
`6.3.2.2
`6.3.3
`6.3.3.1
`6.3.3.2
`6.3.4
`6.3.5
`6.3.6
`6.3.7
`6.4
`6.4.1
`6.5
`
`Zaprinast 150
`Purinones 150
`Pyrazolopyrimidinone PDE5 Inhibitors 151
`Pyrazolo[3,4-d)Pyrimidin-4-0ne PDES Inhibitors 151
`l ,6-Dihydro-7H-Pyrazolo[4,3-d)Pyrimidin-4-One PDES Inhibitors 152
`Imidazotriazinone PDES Inhibitors 154
`Imidazoquinazolinones 155
`Pyrazolopyridopyrimidines 156
`Miscellaneous Heterocylic-Fused Pyrin1idinone PDES Inhibitors 156
`Nonpyrimidonc PDES Inhibitors 160
`Hexahydropyrazino-Pyrido-Indole-1,4-Diones 160
`Conclusions 162
`References 162
`
`7
`
`7.1
`7.2
`7.3
`
`7.4
`7.5
`7.6
`7.7
`7.8
`7.9
`7.10
`7.11
`7.12
`7.13
`
`8
`
`8.1
`8.2
`
`8.2.1
`8.2.1.1
`8.2.2
`8.2.3
`8.2.3.1
`8.2.3.2
`8.3
`8.3.1
`
`Rifamycins, Antibacterial Antibiotics and Their New A pplications 173
`Enrico Selva and Giancarlo Loncini
`Discovery of the Pioneer Drug 173
`Clinically Used Rifamycins 173
`Mode of Action o[ Rifamycins and Structural Requirements
`for Activity 174
`Modulation of Chemotherapeutic Properties 177
`Profiles of Rifamycins Targeted at Tuberculosis Treatment 177
`Rifampicin (INN), Rifampin (USAN) 178
`Rifapentine 180
`Rifabutin 181
`Rifamycins Beyond Tuberculosis 181
`Rifamycin SV and Rifamide 182
`Rifaximin 182
`Trials for Other Therapeutic Indications 183
`Summary 183
`References 184
`
`Monoterpenoid Indole Alkaloids, CNS and Anticancer Drugs 189
`Andras Nemes
`Introduction 189
`Vincamine and Derivatives: Cerebrovascular and Neuroprolective
`Agents 190
`Medicinal Chemistry of Vincamine Derivatives 190
`Structure-Activily Relationships 192
`Synthesis o[ Yincamine Derivatives 193
`Pharmacological Properties of Vincamine Derivatives 193
`Mechanism of Action 193
`Clinical Pharmacology 194-
`Antitumor Dimeric Vinca Plkaloids 195
`Medicinal Chemistry of Dimeric Vinca Alkaloid Derivatives 195
`
`MPI EXHIBIT 1033 PAGE 7
`
`

`

`Contents I ix
`
`8.3.1.1
`8.3.2
`8.3.3
`8.3.3.1
`8.3.3.2
`8.4
`8.4.1
`8.4.1.1
`8.4.2
`8.4.3
`8.4.3.1
`8.4.3.2
`8.5
`
`I 96
`Structure-Activity Relationships
`Synthesis of Dimeric Vinca Alkaloid Derivatives 198
`Pharmacological Properties ofDimeric Vinca Alkaloid Derivatives 199
`Mechanism of Action 199
`Clinical Pharmacology 199
`Antitumor Camptothecin Derivatives 201
`Medicinal Chemistry of Camptothecin Derivatives 201
`Structure-Activity Relationships 202
`Synthesis of Camplothecin Derivatives 203
`Pharmacological Properties of Camptothecin Derivatives 204
`Mechanism of Action 204
`Clinical Pharmacology 205
`Summary and Conclusions 207
`References 207
`
`9
`
`9.1
`9.2
`9.3
`9.4
`9.5
`9.6
`9.7
`
`10
`
`10.1
`10.2
`10.3
`10.4
`10.S
`10.6
`
`10.7
`10.8
`10.9
`
`11
`
`11.1
`11.2
`
`Anth racyclines, O ptim iz ing Antica ncer An:aloguas 217
`Federico-Maria Arcamone
`Introduction: Biosynthetic Antitumor Anlhracyclines 217
`Analogues with Modification of the Aminosugar Moiety 219
`Analogues with Modifications in the Anthraq uinone Moiety 223
`Analogues Modified on Ring A of the Aglycone 226
`Disaccharide Analogues 229
`Other Compounds 232
`Summary and Final Remarks 233
`References 234
`
`Paclitaxel and Epothilone Analogues, Anticancer Drugs 243
`Paul W. Erhardt and Mohammad EI-Dakdouki
`Introduction 243
`Discovery and Development of Paclitaxel 243
`Clinical Success and Shortcomings of Paclitaxel 245
`ABDO Leading to Docetaxel 247
`Additional Structural Analogues 249
`The Pursuit of Microtubule-Stabilizing Pharmacological
`Analogues 250
`The Epothilones 252
`ABDO and Development Leading to Ixabepilone 258
`Conclusions 260
`References 263
`
`Selective Serotonin Reuptake Inhibitors for the Treatment
`of Depression 269
`Wayne E. Childers Jr. and David P. Rotella
`Introduction 269
`Neurochemistry and Mechanism or Action 270
`
`MPI EXHIBIT 1033 PAGE 8
`
`

`

`xi Contents
`11.3
`11.3.1
`11.3.2
`11.3.3
`11.3.4
`11.3.5
`11.4
`11.4.1
`11.4.2
`11.4.3
`11.4.4
`11.4.5
`11.S
`11.6
`
`12
`
`12.1
`12.2
`12.3
`12.3.1
`12.3.2
`12.3.3
`12.3.4
`
`12.4
`
`12.4.1
`
`12.4.2
`12.5
`12.6
`
`12.7
`
`13
`
`13.1
`13.2
`13.3
`
`13.4
`
`Preclinical Pharmacology 271
`Sertraline 271
`Escitalopram 272
`Fluvoxamine 273
`Fluoxetine 274
`Paroxetine 275
`Medicinal Chemistry 276
`Sertraline 276
`Escilalopram 278
`Fluvoxaminc 279
`Fluoxetine 281
`Paroxetine 284
`Comparison of SSRis and Other Uses 285
`Summary 288
`References 288
`
`Muscarinic Receptor Antagonists in the Treatment ofCOPD 297
`Matthias Crauert, Michael P. Pieper, and Paa/a Casarosa
`Introduction 297
`Muscarinic Receptor Subtypes 298
`Structures of Muscarinic Agonists and Antagonists 299
`Muscarinic Agonists 299
`Antimuscarinics 300
`Discovery of Quaternary Antimuscarinics 303
`Once-Daily Quaternary Antimuscarinics: Tiotropium Bromide
`as the Gold Standard 305
`Preclinical Pharmacology: Comparison of Ipratropium
`and Tiotropium 309
`Bronchoconstriction in Conscious Guinea Pigs According
`to the Method of Kallos and Pagel 310
`Bronchoconstriction in Anaesthetized Dogs 310
`Clinical Pharmacology 311
`Antimuscarinics in Clinical Development for the Treatmenf
`ofCOPD 313
`Summary 313
`References 314
`
`(:S-Adrenoceptor Agonists and Asthma 319
`Giovanni Gaviraghi
`Introduction 319
`First-Generation ~i-Agonists: The Short-Acting Bronchodilators 319
`Second-Generation PrAgonists: Further Derivatives
`of Salbutamol 321
`Third-Generation Pz-Agonists: The Long-Acting
`Bronchodilators 321
`
`MPI EXHIBIT 1033 PAGE 9
`
`

`

`Contents I XI
`
`13.5
`13.6
`
`Combination Therapy with LABA and Corticosteroids 326
`Future Directions: Once-a-Day nerapy and Bifunctional Muscarinic
`Antagonist- ~i-Agonist (MABA) 327
`References 329
`
`Part Ill
`
`Case Histories 333
`
`14
`
`14.1
`14.2
`14.2.1
`14.2.2
`14.2.3
`14.2.4
`14.3
`
`15
`
`15.1
`15.2
`15.3
`15.4
`15.5
`15.6
`15.7
`
`16
`
`16.1
`16.1.1
`16.2
`16.2.1
`16.2.2
`16.3
`16.4
`16.4.1
`16.5
`16.6
`16.7
`16.8
`16.9
`16.9.1
`
`Liraglutide, a G LP-1 Analogue to Treat D iabetes 335
`Lotte B. Knudsen
`Introduction 335
`Discussion 338
`Physiology of Native GLP-1 338
`Development ofLiraglutide: A GLP-1 Analogue 339
`The Pharmacology of Llraglutide 346
`Clinical Evidence with Liraglutide 349
`Summ:iry 350
`References 351
`
`Eplerenone: Selective Aldoste.rone Antagonist 359
`Jaros/av Kolvoda and Marc de Gasparo
`Introduction 359
`Development of a Specific and Selective Aldosterone Antagonist 360
`Eplerenone: Selectivity and Specificity 367
`Preclinical Development ofEplerenone: From Animal to Man 373
`Further Development of Eplerenone 375
`Conclusions 376
`Epilogue 376
`References 377
`
`Clevudine, to Treat H epatitis B Viral Infection 383
`Ashoke Sharon, Ashok K.Jha, and Chung K. Chu
`Current Status of Anti-HBV Agents 383
`Nucleoside Reverse Transcriptase Inhibitors 386
`Chemical Evolution of Clevudine 387
`Development of Synthetic Routes 387
`Structure-Activity Relationships 388
`Metabolism and Mechanism of Action 390
`Pharmacokinetics 392
`Woodchuck Studies 393
`Clinical Studies 394
`Drug Resistance 396
`Toxicity and Tolerability 398
`Dosage and Administtation 399
`Combination Therapy 399
`Combination of Clevudine ""<ilh Other Agents 399
`
`MPI EXHIBIT 1033 PAGE 10
`
`

`

`XII I Contents
`
`16.9.2
`16.10
`
`17
`
`17.1
`17.2
`17.2.1
`17.2.2
`17.2.3
`17.3
`17.3.1
`
`17.3.2
`
`17.3.3
`17.3.4
`17.4
`17.5
`17.6
`17.7
`
`18
`
`18.1
`18.2
`18.2.1
`18 .3
`18 .3.1
`18 .3.2
`18 .3.3
`18 .3.3.1
`18.3.3.2
`18.3.3.3
`18.4
`18.4.1
`18.4.2
`18.4.3
`18.5
`18.6
`
`Combination of Clevudine with Vaccine 400
`Summary 400
`References 401
`
`Rilpivirine, a Non-nucleoside Reverse Transcriptase Inhibitor
`to Treat HIV-1
`409
`Jerome Guil/emont, Luc Geeraert, Jan Heeres, and Paul j. Lewi
`Introduction 409
`Chemistry 412
`Synthesis ofTMC278 and Close Analogues 412
`Modulation of the Central Heterocycle Core 4.J8
`C-5 Substilu tion of the Pyrimidine Core 419
`Structure- Activity Relationships 420
`Introduction of G Spacer Between the Ary! Ring
`and the Cyano Group 421
`Modub.tion of Substituents at C-2 and C-6 on the Left Wing
`and of the Linker Belween Left Wing and Pyrimidine Core 423
`Subsitution at C-5 Position of the Pyrimidine Heterocycle 424
`Modification of the Central Heterocycle Core 426
`TMC278: Physicochemical Properties 429
`Modeling ofTMC278 and Crystal Structure 430
`Pharmacokinelic and Phase II Studies ofTMC278 431
`Conclusions 434
`References 434
`
`Tipranavir, a Non-Peptidic Protease Inhibitor for Multi-drug
`Resistant HIV 443
`Suvit Thaisrivongs, Joseph W. Strohbach, and Steve R. Turner
`Human Immunodeficiency Virus 443
`HIV Protease 443
`HIV Pis 444
`Approaches to Identifying and Developing PI Leads 446
`Focused Screening 446
`Broad Screening for Nonpeptidic Leads 447
`Structure-Based Drug Design 448
`PNU-96988, A First-Generation Clinical Candidate 449
`PNU-103017, A Second-Generation Clinical Candidate 450
`Tipranavir, The Third Generation 453
`Characteristics ofTipranavir 454
`in Vitro Activity
`454
`Pharmacokinetics 455
`Highlights of Clinical Data 456
`Fragment-Based Lead Development? 457
`Summary 458
`References 459
`
`MPI EXHIBIT 1033 PAGE 11
`
`

`

`Contents I XIII
`
`19
`
`19.1
`19.2
`19.3
`
`19.4
`19.4.1
`19.4.2
`19.4.3
`19.S
`19.6
`19.7
`
`20
`
`20.1
`20.2
`20.3
`
`Lapatinib, an Anticancer Kinase Inhibitor 465
`Karen Lackey
`Introduction 465
`Aims 467
`Chemical Evolution and Proof-of-Mechanistic Approach
`Using Small Molecules 469
`Final Set of Analogues that Led to the Discovery ofLapatinib 474
`6-Furanyl Quinazoline Series 474
`6-Thiazolylquinazoline Series 479
`Alkynylpyrimidine Series 480
`Final Selection Criteria and Data 482
`Early Clinical Results 487
`Prospects for Kinase Inhibitors 489
`References 490
`
`Das:atinib, a Kinas:o Inhibitor to Treat Chronic Myologonous
`Leukemia 493
`Jagabandnu Das and Joel C. Barrish 493
`Introduction 493
`Discussion 494
`Clinical Findings and Summary 502
`References 503
`
`21
`
`21.1
`21.2
`21.3
`21.4
`21.4.1
`21.4.2
`21.4.3
`21.4.4
`21.S
`21.6
`21.7
`
`Venlafaxine and Desvenlafaxine, Selective Norepinephrine
`and Serotonin Reuptake Inhibitors to Treat Major
`Depressive Disorder 507
`Magid Abou-Gharbia and Wayne E. Childers Jr.
`Introduction 507
`Major Depressive Disorder 510
`MDD Pharmacotherapy 511
`The Discovery ofVenlafaxine 511
`Identification of an Early Lead (WY-44362} 511
`Structure-Activity Relationship Studies 512
`In Vivo Animal Models of Preclinical Efficacy 514
`Selection ofWY-45030 for Clinical Trials 514
`Clinical Efficacy of Effexor® 515
`An Extended Release Fonnulation - Effexor XR~9 516
`Discovery of a Second-Generation SNRI -
`0 -Desmethylvanlafaxine 516
`21.8
`Effexor and Pristiq - Additional Considerations 518
`21.8.1
`Effexor 518
`21.8.1.1 Onset of Action 518
`21.8.1.2 Treatment of Some Anxiety Disorders 519
`21.8.1.3
`Painful Somatic Symptoms 519
`21.8.2
`Pristiq 519
`
`MPI EXHIBIT 1033 PAGE 12
`
`

`

`XIV I Contents
`
`21.8.2.1 Anxiety and Painful Symptoms 519
`21.8.2.2 Symptoms Associated with Menopause 519
`21.9
`Conclusions 520
`References 520
`
`Index 525
`
`MPI EXHIBIT 1033 PAGE 13
`
`

`

`Abbreviations
`
`ABC
`ABDD
`ABPM
`ACAT
`ACE
`ACTH
`ADMET
`AFC
`AIDS
`ALT
`ALL
`AMP
`cAMP
`ANDA
`Cl-APA
`APV
`AR
`ATP
`AUC
`AZT
`BBB
`Bcr-Abl
`BG
`b.i.d.
`BOC
`CBF
`CCso
`P-CCE
`CGI
`CHB
`CK
`CL
`CLR
`
`ATP binding cassette
`analogue-based drug discovery
`ambulatory blood pressure monitoring
`acyl-CoA:cholesterol ~cyltr1r1sfense
`angiotensin-converting enzyme
`adrenocorticotropic hormone
`absorption, distribution, metabolism, excretion and toxicity
`7-amino-4-trifiuorome thylcoumarin
`acquired immunodeficiency syndrome
`alanine aminotransferase
`acute lymphoblastic leukemia
`amprenavir
`cyclic 3' ,S'-adenosine mono phosphate
`Abbreviated New Drug Application
`cr-anilinophenylacetamide
`amprenavir
`androgen receptor
`adenosine triphosphate
`area under the curve
`azidothymidine
`blood-brain-barrier
`Breakpoint cluster region - Abelson
`blood glucose
`twice a day (from Latin bi, in die)
`1-butoxycarbonyl
`cerebral blood flow
`50% cytotoxic concentration
`ethyl P-carboline-3-carboxylate
`Clinical Global Impressions Scale
`duonic hepatitis B
`creatine kinase
`clearance
`renal clearance
`
`Analogue-basal Dr..g Discovery II. Edited by Janos Fischer and C. Robin Gancllin
`Copyright© 2010 WILEY-VCJ-1 Verlag Gmbl-1 & Co. KGaA, Wcinhcim
`ISBN: 978-3-527-32549-8
`
`MPI EXHIBIT 1033 PAGE 14
`
`

`

`xx11 I Abbreviations
`
`CLr
`CLY
`CLV-TP
`CML
`CMRglc
`CNS
`COBP
`COPD
`COX-1
`COX-2
`CPI/r
`CPT
`CRC
`CYP
`DA
`10-DAB
`DAPY
`DATA
`dCK
`DNA
`cDNA
`cccDNA
`mtDNA
`DOC
`DOCA
`DPP-4
`DSM-III
`
`EBV
`EC50
`ED
`EFS
`EGFR
`EMEA
`EPA
`EPO
`EPS
`Erk
`ETC
`FAAH
`FBDD
`FDA
`L-FEAU
`FEV
`L-FMAU
`
`total clearance
`devudine
`devudine triphosphate
`chronic myelogenogenous leukemia
`cerebral metabolic rate of glucose
`central nervous system
`duonic obstructive brond10-pneumopathies
`chronic obstructive pulmonary disease
`cyclooxygenase-1
`cyclooxygcnasc-2
`comparator protea,e inhibitor boosted with ritonavir
`camptothecin
`colorectal cancer
`cytochrome P4S0 isoenzyme
`dopamine
`10-deacetyl-baccatin
`diarylpyrimidine
`diaryltriazine
`deoxycytidine kinase
`desoxyribonucleic acid
`complementary deoxyribonucleic acid
`covalently closed circular DNA
`mitochondrial DNA
`deoxycorticosterone
`deoxycorticosterone acetate
`dipeptidyl peptidase 4
`Diagnostic and Statistical Manual of Mental Disorders,
`third edition
`Epstein-Barr virus
`effective concentration 50
`erectile dysfunction
`electric field stimulation
`epidermal growth factor receptor
`European Medicines Agency
`Environmental Protection Agency
`European Patent Office
`exprapyramidal side effect
`extracellularly regulated kinase
`emtricitabine
`fatty acid amide hydrolase
`fragment-based drug design
`Food and Drug Administration
`1-(2' -deoxy-2' -fluoro-P-L-arabinofuranosyl)-5-ethyluridine
`forced expiratory volume
`L-2' -fluoro-5-melhyl-P-L-arabinofuranosylw·acil
`
`MPI EXHIBIT 1033 PAGE 15
`
`

`

`Abbreviations I XXIII
`
`GABAA
`GAD
`GI
`GIP
`GLP-1
`cGMP
`GPilb/Illa
`HA
`HAART
`HA/ACTH
`HAM-A
`HAM-D
`HbA1c
`HBV
`HBcAg
`HBeAg
`HbsAg
`HCC
`HCV
`HDV
`hERG
`HFB
`HIAA
`HIV
`HIV PR
`HMG-CoA
`5-HT
`5-HTP
`HTS
`IBMX
`ICso
`p!Cso
`res
`IDR
`IDV
`i.m.
`IND
`INN
`lOPY
`i.p.
`i.v.
`Ki
`LABA
`Lek
`hLck
`
`gamma-aminobutyric acid A
`generalized anxiety disorder
`growth inhibition
`glucose-dependent insulinotropic polypeptide
`glucagon-like peptide-I
`cyclic 3' ,S'-guanosine mono phosphate
`glycoprotein lib/ Illa
`heavy atom
`Highly Active Antiretroviral Therapy
`his tamine-induced adrenocorticotropic hormone
`Hamilton Anxiety Taring Scale
`Hamilton Depression Rating Scale
`glycosylated haemoglobin
`hepatitis B virus
`hepatitis B core antigen
`hepatitis B e antigen
`hepatitis B surface antigen
`hepatocellular carcinoma
`hepatitis C virus
`hepatitis delta virus
`human ether-a-go-go-related gene
`human foreskin fibroblast
`5-hydroxy-indole acetic acid
`human immunodeficiency virus
`HIV protease
`3-hydroxy-3-methylglutaryl coenzyme A
`5-hydroxytryptamine (serotonin)
`5-hydroxytryptophan
`high-throughput screening
`isobutylmethylxanthine
`inhibitory concentration SO
`- log ICso
`inhaled corticosteroids
`idarubicin
`indinavir
`intramuscular
`lnvestigational New Drug
`International Nonproprietary Name
`iodophenoxypyridone
`intra peritoneal
`intravenous
`inhibitory constant
`long-acting fu-agonist
`lymphocyte specific kinase
`human Lek
`
`MPI EXHIBIT 1033 PAGE 16
`
`

`

`XXIV I Abbreviations
`
`mLck
`LDL-C
`LE
`LPV
`LVEF
`MADRS
`MAOI
`M1
`MAP
`rMD
`MDD
`MDR
`MED
`MES
`MIC
`MR
`MRP
`MTD
`NAPQI
`NCE
`NCI
`NDA
`NE
`NMR
`NNRTI
`NO
`NPs
`NPClLl
`NR!s
`NRTI
`NSAIDs
`NSCLC
`OADs
`oc
`OCD
`OGTT
`PCA
`PCF
`PCT
`PDEs
`PDGFR
`PEP
`PGE1
`PGE2
`P-gp
`
`murine Lek
`low-density lipoprotein-cholesterol
`ligand efficiency
`lopinavir
`left ventticular ejection fraction
`Montgomery-Asberg Depression Rating Scale
`monoarnine oxidase inhibitor
`muscarinic receptor M1 subtype
`mitogen-activated protein
`restrained molecular dynamics
`major depressive disorder
`multidrug resistance
`minimal effective dose
`maximal electroshock seizure
`minimal inhibitory concentration
`mineralocorticoid receptor
`multidrug resistance-associated protein
`maximum tolerated dose
`N-acetyl-p-benzoquinone imine
`New Chemical Entity
`National Cancer Institute
`New Drug Application
`norepinephrine
`nuclear magnetic resonance
`nonnucleoside reverse transcriptase inhibitor
`nitric oxide
`natural products
`Niemann-Pick Cl-Like-1
`norepinephrine reuptake inhibitors
`nucleoside reverse transcriptase inhibitor
`nonsteroidal anti-inflammatory drugs
`non-small cell lung cancer
`oral antidiabetic drugs
`ovarian cancer
`obsessive-compulsive disorder
`oral glucose tolerance test
`p-chloroamphetarnine
`plant cell fermentation
`Patent Cooperation Treaty
`phosphodiesterases
`platelet derived growth factor receptor
`prolyl endopeptidase
`prostaglandin E1
`prostaglandin E2
`permeability glyocoprotein
`
`MPI EXHIBIT 1033 PAGE 17
`
`

`

`Abbreviations I XXV
`
`Ph(+)
`PK
`PKG
`POMS
`PPCE
`PR
`QSAR
`q.d. or QD
`RBA
`RGD
`RNA
`RNApol
`mRNA
`RT
`RTV
`SAR
`SBDD
`s.c.
`SCIO
`SCLC
`SEDDS
`SEF
`SI
`SIV
`SMC
`SNRI
`SQV
`Src
`SRI
`SSRls
`TCR
`TDF
`TGfo
`Tl
`TIBO
`
`t.i.d.
`TK
`TMPK
`TPV
`TPV/r
`TPT
`TRIPs
`TIP
`UDP
`
`Philadelphia chromosome positive
`pharma.kokine tic
`protein kinase G
`profile of mood state
`postproline cleaving enzyme
`progesterone receptor
`q uantilative struclure-actiYily relationship
`once a day (from Latin quaque die)
`relative binding affinity
`arginine-glycine-as partic acid
`ribonucleic acid
`RNA polymerase
`messenger RNA
`reverse transcriptase
`ritonavir
`structure-:i.ctivity rebtionship
`structure-based drug design
`subcutaneous
`severe combined immunodeficient
`small-cell lung cancer
`self-emulsifying drug delivery system
`sodium excreting factor
`selectivity index
`simian immunodeficiency virus
`smooth muscle cell
`serotonin/ norepinephrine reupta.ke inhibitor
`saquinavir
`sarcoma
`serotonin reupta.ke inhibitor
`selective serotonin reuptake inhibitors
`T-cell antigen receptor
`tenofovir disoproxil fumarate
`tansforming growth factor-ex
`tumor inhibition
`4,5 ,6,7 -tetrahydro-5-methylimidazo(4,5, 1-jk]benzodiazepin-2
`(lH)-one
`lhree times daily
`lhymidine kinase
`lhymidylate kinase
`tipranavir
`tipranavir/ritonavir combination
`Lopotecan
`Trade-related Aspects of Intellectual Property Rights
`tune to progression
`uridine diphosphate
`
`MPI EXHIBIT 1033 PAGE 18
`
`

`

`XXVI I Abbreviations
`
`UGT
`USAN
`VEGFR
`VMS
`VSMC
`Vss
`W BC
`WHcAg
`WHsAg
`WHV
`WTO
`
`uridine diphosphate glucuronyl transferase
`United States Adopted Names
`vascular endothelial growth factor receptor
`vasomotor symptoms
`vascular smooth muscle cell
`s teady-state volume
`white blood cell
`woodchick hepatitis virus core antigen
`woodch uck hepatitis virus surface antigen
`woodch uck hepatitis virus
`World Trade Organization
`
`MPI EXHIBIT 1033 PAGE 19
`
`

`

`14
`Liraglutide, a CLP-1 Analogue to Treat Diabetes
`Lotte B. Knudsen
`
`14.1
`lntroduct.ion
`
`The therapeutic potential of glucagon-like peptides (GLPs), particularly glucagon-like
`peptide-1 (GLP-1), is only now beginning to be realized at the start of the twenty-first
`century. It was, however, the discovery of secretin in 1902 by Bayliss and Starling [1]
`that initiated interest in the endocrine function of the gut and pancreas. These
`scientists speculated that signals arising from the gut could elicit an endocrine
`response affecting carbohydrate disposal. In 1929, Zunz and LaBarre described an
`intestinal extract that could produce hypoglycemia [2], and in a separate paper,
`LaBarre used the term "incretin" to describe activity in the gut that might stimulate
`pancreatic endocrine secretions [3]. Despite initial interest in "incretin," research
`virtually stopped in this area due to the outbreak of World War II and the publication
`of several negative papers by Ivy and colleagues [4-6). Twenty-five years later,
`McIntyre suggested that a humoral subs tance was released from the jejunum during
`glucose absorption, acting in concert with glucose to stimulate insulin release from
`pancreatic ~-cells [7]. In 1969, Unger and Eisentraut referred to the gut- pancreas
`association as the enteroinsular axis [8), and this axis was subsequently described as
`involving nutrient, neural, and hormonal signals from the gut lo the pancreatic islet
`cells. To be termed an "increlin," any substance acting on this patJ1way must be
`secreted in response to nutrient stimuli and must stimulate glucose-dependent
`insulin secretion [9).
`A second incretin hormone, following the discovery of glucose-dependent in(cid:173)
`sulinotropic polypeptide (GIP), was postulated lo exist as a consequence of the
`doningof cDNAs encoding the preproglucagon gene in anglerfish pancreas [10-12].
`Habener and colleagues conducted some of the very early work to characterize
`preproglucagon, but it was Bell who first identified GLP-1(1-37) [13]. In 1986/ 1987, it
`was discovered that the truncated forms, GLP-1(7-37) and (7-36)amide, were the
`active insulinotropic isoforms of G LP-1 [14, 15]. Lowering of blood glucose with G LP-
`1 was first shown in three studies by Nathan, Nauck, and Kreymann [16- 18], with the
`
`Analogue-basal Dr..g Discovery II. Edited by Janos Fischer and C. Robin Gancllin
`Copyright© 2010 WILEY-VCJ-1 Verlag Gmbl-1 & Co. KGaA, Wcinhcim
`ISBN: 978-3-527-32549-8
`
`MPI EXHIBIT 1033 PAGE 20
`
`

`

`

`

`14. l Introduction 1337
`
`The binding affinity and biological activity are particularly affected by His on
`position 7, Glyon position 10, Phe on position 12, Thr on position 13, Asp on position
`15 (all directly involved in receptor interaction), Phe on position 28, and Ile on
`position 29 (21]. The conformation ofGLP-1 includes an N-terrninal random coil and
`two helical segments joined by a linker region; this closely resembles the structure of
`glucagon (22].
`The preproglucagon gene is expressed in several cell types in the body. The
`pancreas contains a - and ~-cells: a -cells process proglucagon and therefore secrete
`glucagon. Only small q uanlities of G LP-1 have been found secreted from pancreatic
`a -cells [23]. Proglucagon and its fragments arc furthermore secreted in the small and
`large bowels. Intestinal L-cells that process proglucagon are the major source of GLP-
`1; these are mainly situated in the distal jejunwn and ileum and also throughout the
`whole intestine. Proglucagon processing occurs in the central nervous system: GLP-1
`is therefore an important neurotransmitter in the brain (24).
`GLP-1 activity is mediated by the G LP -1 receptor, a class 2, G-protein-coupled
`receptor (25). This receptor is found in m:i.ny organs including the p:mcrea£,
`s tomach, intestines, and parts of the peripheral and central nervous systems, and
`these are the main therapeutic targets (26, 27). GLP-1 receptors have been found in
`other tissues that may be relevant for its therapeutic effect, namely, the kidneys,
`endothelium. small blood vessels, and heart (28-31). Due to the organ systems that
`GLP-1 acts on, it is an attractive therapeutic target for type 2 diabetes mellitus
`and obesity.
`For example, in pancreatic ~-cells, GLP-1 receptor activation increases adenylate
`cyclase activity that leads to glucose-dependent insulin secretion [14, 18]; in addition,
`GLP-1 exerts a glucose-dependent, suppressive effect on glucagon secretion [32].
`Both effects act to lower blood glucose levels. Indeed, glucagon antagonism has long
`been suggested as a treatment for both type 1 and type 2 diabetes [33). Together with
`glucose, G LP-1 acts on the ~-cell to promote insulin gene transcription and therefore
`promotes insulin synthesis [34]; furthermore, GLP-1 can restore the ~-cell's sen(cid:173)
`sitivity to glucose, thereby improving ~-cell function [35]. In addition, there are
`animal studies that support a "protective" ~-cell effect of GLP-1, with apoptosis
`s uppression, neogenesis and proliferation stimulation, and increases in ~-cell
`mass [36, 37].
`Furthermore, G LP-1 has advantageous gastrointestinal effects: gastric emptying is
`slowed following meal consumption [38) and it reduces gastric acid secretion [39],
`thus enabling food to be processed slowly. Studies have shown that GLP-1 infusion
`can reduce hunger sensations ( 40]. Consequently, a beneficial effect on body weight
`may be expected with any therapeutic application of GLP-1 [41 ).
`An additional effect of GLP-1 that is of potential therapeutic interest is its actions
`on the cardiovascular system. Mostly based on animal data, it is thought that GLP-1
`improves myocardial and endothelial function (42, 43) and GLP-1 may also directly
`protect the myocardium [29].
`With these above effects, it is obvious to see why research in type 2
`diabe tes mellitus has focused on GLP-1 as an exciting therapeutic possibility
`(Figure 14.3) .
`
`MPI EXHIBIT 1033 PAGE 22
`
`

`

`

`

`14.2 Discussion 1339
`
`GLP-1 and its metabolites are mainly cleared via the kidney through glomerular
`filtration and renal catabolism 153]. This renal elimination does mean that in patients
`with renal failure or insufficiency, accumulation of GLP-1 levels can occur 154, 55].
`Fasting plasma levels ofGLP-1 appear to range between 5 and 10 pmol/1, and in
`healthy individuals increase to approximately 30 pmol/1 after food intake (47). The
`postprandial increase in GLP-1 levels depends on the size of the meal (56). Some data
`suggest GLP-1 secretion in patients with type 2 diabetes is impaired compared to
`healthy individuals (47, 56): healthy individuals have a significantly greater and more
`prolonged G LP-1 response, with levels peaking at around 90-120 min [ 4 7]. However,
`the effect is small and contradicted in other studies, so this probably docs not have
`much significance. Much more important is tbat the other main incretin, GIP, only
`induces a very small release of insulin in patients with diabetes compared to
`healthy individuals in whom CLP-1 and GIP have more equal effects (57]. Thus,
`in patients there is a lack ofinsulin secretion from C IP that pharmacological levels of
`GLP-1 may restore.
`
`14.2.2
`Development of Liraglutide: A G LP-1 Analogue
`
`Given the pharmacokinetic pro