Table Of Content1
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2 ACS SYMPOSIUM SERIES
ACS
SYMPOSIUM
RC B COMPLETE ACCOUNTS
SERIES
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VOLUME 1332 NP O OF INTEGRATED DRUG
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STORIES OF DRUGS FROM THE BENCH SN
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These engaging accounts walk readers through the drug discovery and T I
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development processes, from identification of a target compound to ET
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the development of large-scale processes. The authors hail from leading PG
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pharmaceutical companies, grounding the text in real-world applications. AA
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These accounts also touch on reaction safety and development costs, ME
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providing insight into often closed-door procedures. These relevant examples C D
from industry are informative to chemists in both industry and academia, ER
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especially those interested in discovering and developing drug candidates. TG
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PUBLISHED BY THE DV
American Chemical Society UE
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SPONSORED BY THE TY
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ACS Division of Organic Chemistry YA
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PESTI, ABDEL-MAGID
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Complete Accounts of Integrated Drug Discovery
and Development: Recent Examples from the
Pharmaceutical Industry
Volume 2
1332
ACS SYMPOSIUM SERIES
Complete Accounts of Integrated Drug Discovery
and Development: Recent Examples from the
Pharmaceutical Industry
Volume 2
Jaan A. Pesti,Editor
EnginZyme AB, Stockholm, Sweden
Ahmed F. Abdel-Magid,Editor
Therachem Research Medilab, LLC, Chelsea, Alabama, United States
Rajappa Vaidyanathan,Editor
Bristol-Myers Squibb, Bangalore, India
Sponsored by the
ACS Division of Organic Chemistry
American Chemical Society, Washington, DC
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Foreword
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ACS Books Department
Contents
Foreword. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi
1. Synthetic Routes for Venetoclax at Different Stages of Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Yi-Yin Ku and Michael D. Wendt
2. Discovery and Development of Lorlatinib: A Macrocyclic Inhibitor of EML4-ALK
for the Treatment of NSCLC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Robert Dugger, Bryan Li, and Paul Richardson
3. From Discovery to Market Readiness: The Research and Development of the β-
Sparing Phosphatidylinositol 3-Kinase Inhibitor Taselisib. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Rémy Angelaud, Steve Staben, Timothy Heffron, Andreas Schuster, and Frédéric St-Jean
4. Discovery and Development of the First Antibody–Antibiotic Conjugate Linker-
Drug. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Stefan G. Koenig and Thomas H. Pillow
5. The Discovery of the Nav1.7 Inhibitor GDC-0276 and Development of an Efficient
Large-Scale Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Andreas Stumpf, Daniel Sutherlin, Christoph M. Dehnhardt, and Rémy Angelaud
6. Discovery and Development of AMG 333: A TRPM8 Antagonist for Migraine. . . . . . . . . . . . . 125
Neil F. Langille and Daniel B. Horne
7. The Discovery and Chemical Development of PF-06273340: A Potent, Selective, and
Peripherally Restricted Pan-Trk Inhibitor for Pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
David C. Blakemore, Thomas Brandt, Craig Knight, and Sarah E. Skerratt
8. Optimization of an Azaindazole Series of CCR1 Antagonists and Development of a
Semicontinuous-Flow Synthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
ChristianHarcken,JoshuaineGrant,HosseinRazavi,MauriceA.Marsini,FredericG.Buono,
Jon C. Lorenz, and Jonathan T. Reeves
9. Discovery and Development of Non-Covalent, Reversible Bruton’s Tyrosine Kinase
Inhibitor Fenebrutinib (GDC-0853). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
James J. Crawford and Haiming Zhang
10. Discovery and Early Development of Small Molecule Proprotein Convertase
Subtilisin/Kexin Type 9 (PCSK9) Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
David W. Piotrowski and Emma L. McInturff
vii
11. Rational Design to Large-Scale Synthesis: Development of GSK8175 for the
Treatment of Hepatitis C Virus Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
Andrew J. Peat and Shiping Xie
Editors’ Biographies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Indexes
Author Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
viii
Foreword
For every drug that is sold on the market, there will be dozens of other drugs that failed
somewhereindevelopment,mostoftenasthebenefit/riskwassimplynotgoodenoughtowarrant
commercialization. Every drug, but also all those which do not crown their development with
commercialization,haveastory.Itstartswithabiologicalhypothesisonthecauseforadisease,the
developmentofbiologicalassays,andaftertheidentificationofthefirsthits,thedevelopmentofthese
toleads.Thencomesthefurtherevolutionoftheleadstocandidatesandthenfinallytheirprogression
throughthemanyphasesofthedevelopment.Andwhenallobstaclesareovercome,ultimatelywe
attain commercialization to serve the patient.
Every step of the way is complex and involves the interplay of many disciplines, making the
discovery and development of a new drug into the biggest and most challenging “science
experiment” one can imagine. Each phase of the genesis of a new drug requires the combination
of significant scientific insight with the ability to find the creative solutions to the problems and
challenges that threaten to derail the process at every step of the way.
Manyscientificdisciplinesareinvolved,butitisthesyntheticchemistthatistheessentialfactor.
Ahighlyremarkableandinsightfuldescriptionoftheuniquenessofchemistryamountthesciences
was already suggested in the 19thcentury by the French scientist Marcellin Berthelot:
“La chimie crée son objet. Cette faculté créatrice, semblable à celle de l’art lui-même,
la distingue essentiellement des sciences naturelles et historiques.” (“Chemistry creates
its object of study. Such a creative power is analogous to the power of art; it essentially
distinguishes chemistry from natural and historical sciences.”)
Marcelin Berthelot, La synthèse chimique
Alcan, Paris, 1887
It clearly describes the central role that we play as chemists. We are the scientists that create.
We are not just descriptive and find ourselves with an insurmountable problem, but we have the
meanstodesignthesolution.Thisisthesamecreativeprocessthatgivesusart,butwechemistsare
providingabeautifullyconceivedandpreparedorganicmolecule.Thebeautyofthecreativesolution
is a molecule with the right properties which ultimately provide the indispensable tool that cures
adisease.Andthecomplexityofthecreativetask,frominitiallydesigningthemoleculetoactually
beingabletomakeitsafelyandeconomicallyinlargeamounts,iscoveredanddescribedforseveral
examplesinthisbook.Thetopicsencompassdrugsthatarecoveringthewholegamutofdiseasesthat
inflictmankind:theyreachfrominfectiousdiseases,systemicdisorders,overpainandCNSdiseases
tovariousmetabolicmalfunctions.Thelonglistofdiseasesclearlydemonstratesthestrongneedfor
better medicines, created and made by organic chemists.
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