Complete accounts of integrated drug discovery and development. Volume 2: recent examples from the pharmaceutical industry PDF
Preview Complete accounts of integrated drug discovery and development. Volume 2: recent examples from the pharmaceutical industry
1 3 3 2 ACS SYMPOSIUM SERIES ACS SYMPOSIUM RC B COMPLETE ACCOUNTS SERIES EO I CM O E L VOLUME 1332 NP O OF INTEGRATED DRUG L TE G ET I XAE A CA DISCOVERY AND L MC PC LO DEVELOPMENT EU STORIES OF DRUGS FROM THE BENCH SN FT RECENT EXAMPLES FROM THE RS O O PHARMACEUTICAL INDUSTRY VOLUME 2 M F These engaging accounts walk readers through the drug discovery and T I N H development processes, from identification of a target compound to ET E the development of large-scale processes. The authors hail from leading PG HR pharmaceutical companies, grounding the text in real-world applications. AA RT These accounts also touch on reaction safety and development costs, ME AD providing insight into often closed-door procedures. These relevant examples C D from industry are informative to chemists in both industry and academia, ER UU especially those interested in discovering and developing drug candidates. TG I C D A I LS C I NO PUBLISHED BY THE DV American Chemical Society UE SR SPONSORED BY THE TY R ACS Division of Organic Chemistry YA N VD O D L UE MV E E L 2O P M E N T PESTI, ABDEL-MAGID eP & VAIDYANATHAN tE aS lT . I 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 Library of Congress Cataloging-in-Publication Data Library of Congress Cataloging in Publication Control Number: 2019033049 ThepaperusedinthispublicationmeetstheminimumrequirementsofAmericanNationalStandardforInformation Sciences—Permanence of Paper for Printed Library Materials, ANSI Z39.48n1984. Copyright © 2019 American Chemical Society AllRightsReserved.ReprographiccopyingbeyondthatpermittedbySections107or108oftheU.S.CopyrightAct isallowedforinternaluseonly,providedthataper-chapterfeeof$40.25plus$0.75perpageispaidtotheCopyright ClearanceCenter,Inc.,222RosewoodDrive,Danvers,MA01923,USA.Republicationorreproductionforsaleofpagesin thisbookispermittedonlyunderlicensefromACS.DirecttheseandotherpermissionrequeststoACSCopyrightOffice, Publications Division, 1155 16th Street, N.W., Washington, DC 20036. Thecitationoftradenamesand/ornamesofmanufacturersinthispublicationisnottobeconstruedasanendorsementor asapprovalbyACSofthecommercialproductsorservicesreferencedherein;norshouldthemerereferencehereintoany drawing,specification,chemicalprocess,orotherdataberegardedasalicenseorasaconveyanceofanyrightorpermission totheholder,reader,oranyotherpersonorcorporation,tomanufacture,reproduce,use,orsellanypatentedinventionor copyrightedworkthatmayinanywayberelatedthereto.Registerednames,trademarks,etc.,usedinthispublication,even without specific indication thereof, are not to be considered unprotected by law. PRINTED IN THE UNITED STATES OF AMERICA Foreword Thepurposeoftheseriesistopublishtimely,comprehensivebooksdevelopedfromtheACS sponsoredsymposiabasedoncurrentscientificresearch.Occasionally,booksaredevelopedfrom symposia sponsored by other organizations when the topic is of keen interest to the chemistry audience. Beforeabookproposalisaccepted,theproposedtableofcontentsisreviewedforappropriate andcomprehensivecoverageandforinteresttotheaudience.Somepapersmaybeexcludedtobetter focusthebook;othersmaybeaddedtoprovidecomprehensiveness.Whenappropriate,overview orintroductorychaptersareadded.Draftsofchaptersarepeer-reviewedpriortofinalacceptanceor rejection. Asarule,onlyoriginalresearchpapersandoriginalreviewpapersareincludedinthevolumes. Verbatim reproductions of previous published papers are not accepted. 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. ix
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