Table Of ContentDrug-Like Properties
Drug-Like Properties
Concepts, Structure, Design, and
Methods from ADME to Toxicity Optimization
By
Li Di
Edward H. Kerns
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Dedication
Li Di dedicates this book to:
My parents: I am infinitely in debt to you
My sisters, Ning and Qing: for being my best friends
My children, Kevin and Sophia: I am very proud of you.
Ed Kerns dedicates this book to:
William, Virginia, Nancy, Patrick, Chrissy,
Brian and Lillian: for your love and support.
Preface
PREFACE TO SECOND EDITION
Overthepasteightyearssincethefirsteditionofthisbookmanyinnovativenewdrugshavebeendiscoveredthroughthe
creativity and persistence of drug discovery scientists. These certainly benefit the life quality and length for millions of
patients and the joy oftheir familiesand friends. Itis aprivilege towork inthisfield.
Aiding this effort are the many new developments inpharmaceuticalsciences and technology. These give improved
understandingof drug delivery, target interaction, efficacy and safety. Many new developments are incorporated in this
second edition. They include:
l deeper understanding of transporters andtheir effects onpharmacokinetics and drug-druginteraction
l consensus on free drugconcentration as the controllerof invivo efficacy
l broader understanding ofmetabolic enzymes
l improvedmodeling ofhumanpharmacokinetics for clinical dosing and safety prediction
l new in vitro and in vivo methods for improved reliability of measurements of drug physicochemical and ADMET
properties
l improvedschemes and methods for blood–brain barrierpenetration
l toxicityindicatorssuchastime-dependentinhibition,safetyindexesandphysicochemicalmarkersofoff-targeteffects
New examples from the medicinal chemistry literature have also been included to illustrate SAR and lead optimization
approaches.
Above all, the purpose of this book is to assist drug discovery scientists through a resource that explains the funda-
mentals,effectsandstrategiestheycanapplyforselectionandoptimizationofdrugdiscoveryleadsandclinicalplanning,
toimprovesuccessindrugdiscoveryandpatienttherapy.Wehavebeengratifiedbythecommentsofindividualswhohave
indicated thatthis book assisted them. To all, we wish drugdiscovery success.
PREFACE TO FIRST EDITION
Drugresearchisafulfillingcareer,becausenewdrugscanimprovehumanhealth,qualityoflifeandlifespan.Forscientists
dedicatedtodrugresearch,itcanalsobeasupremelychallengingmission,owingtothenumerousattributesthatmustbe
simultaneously optimized to arrive at an efficacious drug-like compound. ADME/Tox (absorption, distribution, metab-
olism,elimination,toxicity)isoneofthesechallenges.Ofthethousandsofnovelcompoundsthatadrugdiscoveryproject
teaminventsandthatbindtothetherapeutictarget,typicallyonlyafractionofthesehavesufficientADME/Toxproperties
tobecomeadrugproduct.Thisbookisdevotedtoprovidingyou,thedrugresearchscientistorstudent,withanintroduction
toADME/Tox property concepts, structure design, andmethodology tohelp you succeedwith these challenges.
Chemistswillbeaidedbythecasestudies,structure–propertyrelationshipsandstructuremodificationstrategiesinthis
book.Theseassistindiagnosingthesubstructuresofaleadstructurethatarenotdrug-likeandsuggestideasforADME/Tox
structuredesign.Overviewsofpropertymethodsprovidethebackgroundneededtoaccuratelyinterpretandapplythedata
forinformeddecisions.ForADME/Toxscientists,insightsonpropertyassaysassistwithselectingmethodsandgenerating
data thatimpactsprojects.
Biologists/pharmacologists will benefit from an increased understanding of ADME/Tox concepts. This is especially
important,becauseinrecentyearstheapplicationofpropertydatahasexpandedfromoptimizinginvivopharmacokinetics
andsafetytobiologicalassays.Lowsolubility,chemicalinstability,andlowpermeabilitycangreatlyaffectbioassaydata.
Equipped with this understanding, biologists are better able to optimize bioassays and include property affects in data
interpretation.
xix
xx Preface
Accordingly, understanding ADME/Tox is important for all drug researchers, owing to its increasing importance in
advancing high quality candidates to clinical studies and the processes of drug discovery. ADME/Tox properties are a
crucial aspect of clinical candidate quality. If the properties are weak, the candidate will have a high risk of failure or
belessdesirableasadrugproduct.ADME/Toxhasbecomeintegratedinthedrugdiscoveryprocessandisatremendous
assetinguidingselectionandoptimizationofpreciousleads.Thisbookisatoolandresourceforscientistsengagedin,or
preparingfor,theselectionandoptimizationprocess.Theauthorswishyousuccessincreatingthepharmaceuticalsofthe
future that will benefit all people.
In preparing thisbook, the authorshad the support and council ofmany drug research colleagues. The leadership of
Magid Abou-Gharbia, Guy T. Carter and Oliver J. McConnell of Wyeth Research, Chemical and Screening Sciences
are greatly appreciated. The careful manuscript review and feedback by Christopher P. Miller was highly beneficial.
The thoughtful comments of several anonymous reviewers are greatly appreciated. LD thanks Prof. Donald M. Small,
Prof.BruceM.Foxman,Prof.RuishengLiforguidance.EKthanksProf.DavidM.Forkey,WilliamL.Budde,andCharles
M. Combs for mentorship. We thank Prof. Ronald T. Borchardt and Christopher A. Lipinski for their friendship,
collaboration, and leadership in the ADME/Tox and medicinal chemistry fields. The enthusiastic feedback of students
intheAmericanChemicalSocietyshortcourseonDrug-likePropertieswashighlyvaluable.Thecollaborativeadventure
of understanding drug-like properties in drug discovery was shared with numerous Wyeth Research colleagues in
PharmaceuticalProfilingand Medicinal Chemistry andtheir respectful, innovative collaboration isgreatly appreciated.
Chapter 1
Introduction
1.1 DRUG-LIKE PROPERTIES IN DRUG DISCOVERY
Drugpropertiescomprisethestructural,physicochemical,biochemical,pharmacokinetic(PK),andtoxicitycharacteristics
ofacompound.Certainvaluesofdrugpropertiesaremoreadvantageousfordiscoveringnewdrugs.Thisconceptadvanced
over many years.Akey article thatdiscussed advantageous propertyvaluescommented:
“Drug-likeisdefinedasthosecompoundsthathavesufficientlyacceptableADMEpropertiesandsufficientlyacceptabletoxicity
propertiestosurvivethroughthecompletionofhumanPhaseIclinicaltrials.”[1]
ADMEisabsorption,distribution,metabolism,andexcretion,theprocessesthatdeterminePK.PhaseIclinicaltrials
measure humansafetyandPK.Thus,“drug-likeproperties”constituteapropertyprofilethatisconsistentwiththedrug
properties of mostcommercial drugs.
Drugpropertiesweretraditionallyafocusofdrugdevelopment.However,inthe1990stheresponsibilityofoptimizing
the drugproperties ofclinical candidateswas given to drugdiscovery scientists. It hasbeen commented:
“…drug-likepropertiesare…intrinsicpropertiesofthemoleculesanditistheresponsibilityofthemedicinalchemiststooptimize
notonlythepharmacologicalpropertiesbutalsothedrug-likepropertiesofthesemolecules”[2]
Drugpropertiesareanintegralpartofdrugdiscovery.Intheearlyphaseofdrugdiscovery,drugpropertiesareusedto
selectthe“hits”thataresuitablestartingpointsforresearchonanewclinicalcandidate.Theyservetofocusdrugdiscovery
effortsintochemicalspacethathasahigherprobabilityofPKandsafetysuccess.Laterindrugdiscovery,theyhavemajor
influences onunderstandingstructure-propertyrelationships (SPR),guidingstructuremodificationsfor propertyoptimi-
zation, diagnosing the causes of inadequate PK and toxicity, optimizing and interpreting bioassays, and building pro-
spective models of human PK and its relationship to pharmacodynamics (PD). Medicinal chemists optimize the drug
propertiesofleadsinparallelwithoptimizingefficacy,selectivity,andnovelty.Thisisaccomplishedbyiterativelymod-
ifying the structure and measuringthe properties ofthe new compound.
As drug discovery scientists extend the science of PK and toxicity, understanding about drug properties and their
complexinfluenceondrugcandidatesexpands.Theearlyfocusonlipophilicity,molecularweight,andhydrogenbonding
hasexpandedtocomplexitiesofproperties,includingsolubility,permeability,metabolicenzymes,andtransporters.The
earlyconceptofdrug-likepropertyrangeshasadvancedtomultiparameteroptimizationapproaches[3],pharmacokinetic/
pharmacodynamic (PK/PD) modeling [4], and physiologically based PK (PBPK) [5]. This mirrors the increasing com-
plexityandsophisticationofallaspectsofdrugdiscovery,whenscientistspursuemultiplelinesofinvestigationinvolving
diversedisciplines.Thefocusisonintegrationofthesedisciplinesthroughcomplexsimultaneousstudiestooptimizeand
select new clinical candidates with abalance ofefficacy, selectivity, PK,and safety [6].
OneexampleofthefundamentalroleofPKandsafetyindrugdiscoveryistheconceptof“threepillarsofsurvival”of
drugcandidatesthroughPhase II[7].The pillars are
“…thefundamentalpharmacokinetic/pharmacodynamicprinciplesofexposureatthesiteofaction,targetbindingandexpression
offunctionalpharmacologicalactivity…”
Drugpropertiesfocusonthefirstpillar,exposureofthedrugatthesiteofaction.Thus,thefieldhasadvancedfrom
generalcharacteristicsofdrugsthatsucceedtodetailedstudyofthecomplexphysicochemistryandbiochemistrythataffect
human PKand safety and effectivelymodelhuman clinical outcomes.
Drug-LikeProperties.http://dx.doi.org/10.1016/B978-0-12-801076-1.00001-0
Copyright©2016ElsevierInc.Allrightsreserved. 1
2 Drug-LikeProperties
1.2 PURPOSE OF THIS BOOK
The various drug properties, terminology, and assays can be overwhelming to drug discovery scientists and students
withoutsufficientintroduction.Sometextsondrugpropertiesaredauntingbecausetheyarewrittenfromtheperspective
of experts in pharmaceutics or drug metabolism/PK and contain detail and mathematical equations that are not easy to
understandfordrugdiscoveryscientists.Thisbookisapracticalguideformedicinalchemists,biologists,pharmacologists,
andstudents.Itprovidesbackgroundmaterialandreal-world,practicalexamplesforpracticingdrugdiscoveryscientists
who need toplan experiments, make sense ofcomplex data, and arrive at informeddecisions.
Thisbookalsoprovidestoolsforworkingwithdrugproperties.First,theinteractionsofdrugmoleculeswiththeinvivo
environmentstheyencounterafteradministrationaredescribed,inordertounderstandwhypropertieslimitdrugexposure
tothe therapeutic target. Next,keydrugproperties are explored (Figure1.1)interms of
Structure- FIGURE1.1 Thisbookequipsdiscoveryscientistsand
Property Property property studentswithapracticalunderstandingofpropertyfunda-
fundamentals effects
relationships mentals,propertyeffects,andstructure-propertyrelation-
ships that can be applied to improving lead series and
biologicalactivity.Literatureexamplesofstructuremodi-
ficationstrategiestoimprovepropertiesaredescribedfor
Discovery chemists to apply to current projects. Information on
Lead scientist property assays provides understanding of the available
methodsandreliableinterpretationofthedata.
Data
Structure
Biological
modification
assays
strategies
Property
Analog
assays
(1) fundamentals of each property;
(2) effects ofeach property on PK, safety, and biological experiments;
(3) SPRcase studies, tosee howstructure affects properties;
(4) structure modificationstrategies, toguide property optimization;
(5) strategiesfor usingthe properties to achieve a quality clinical candidate;
(6) effects ofproperties on invitro andin vivo biological measurements;
(7) descriptionof property methods, for accurate measurement and application of the data.
Theseequipdrugdiscoveryscientistsforincreasedeffectivenessinleadselection,leadoptimization,andtheenhancement
ofdrug discovery biologyand pharmacology assays.
Property-related concepts are described with a minimum of math and emphasis on practical application. Specific
propertyapplicationsindiagnosingpoorPK,designingprodrugs, andformulationfor invivo dosingarealsodiscussed.
AschemefortheworkflowofthisbookisshowninFigure1.1.Drugdiscoveryhasdiverseelementsthatmustbedel-
icately integrated and balanced. Drug properties are important characteristics that help to achieve a quality clinical
candidate.
PROBLEMS
(1) Define the term “drug-like”.
(2) What are two major lead optimization areas indrug discovery?
(3) How can understandingcompound properties assist drugdiscovery biologists?
(4) Compoundpropertiescanaffectwhichofthefollowing:(a)pharmacokinetics,(b)bioavailability,(c)IC ,(d)safety?
50
Introduction Chapter 1 3
REFERENCES
[1] C.A.Lipinski,Drug-likepropertiesandthecausesofpoorsolubilityandpoorpermeability,J.Pharmacol.Toxicol.Methods44(2000)235–249.
[2] R.T.Borchardt,Scientific,educationalandcommunicationissuesassociatedwithintegratingandapplyingdrug-likepropertiesindrugdiscovery,
In:R.T.Borchardt,E.H.Kerns,C.A.Lipinski,D.R.Thakker,B.Wang(Eds.),PharmaceuticalProfilinginDrugDiscoveryforLeadSelection,AAPS
Press,Arlington,2004.
[3] T.T.Wager,X.Hou,R.R.Verhoest,A.Villalobos,Movingbeyondrules:Thedevelopmentofacentralnervoussystemmultiparameteroptimization
(CNSMPO)approachtoenablealignmentofdruglikeproperties,ACSChem.Neurosci.1(2010)435–449.
[4] J.Gabrielsson,A.R.J.Green,Quantitativepharmacologyorpharmacokineticpharmacodynamicintegrationshouldbeavitalcomponentinintegrative
pharmacology,J.Pharmacol.Exp.Ther.331(2009)767–774.
[5] M.Rowland,C.Peck,G.Tucker,Physiologically-basedpharmacokineticsindrugdevelopmentandregulatoryscience,Annu.Rev.Pharmacol.
Toxicol.51(2011)45–73.
[6] D.Li,E.H.Kerns,G.T.Carter,Drug-likepropertyconceptsinpharmaceuticaldesign,Curr.Pharm.Des.15(2009)2184–2194.
[7] P.Morgan,P.H.VanDerGraaf,J.Arrowsmith,D.E.Feltner,K.S.Drummond,C.D.Wegner,S.D.A.Street,Cantheflowofmedicinesbeimproved?
FundamentalpharmacokineticandpharmacologicalprinciplestowardimprovingphaseIIsurvival,Drug.Discov.Today17(2012)419–424.
Chapter 2
Benefits of Property Assessment and Good
Drug-Like Properties
2.1 INTRODUCTION
Drugdiscoveryiscontinuouslyadvancingasnewfundamentalknowledge,methods,technologies,andstrategiesareintro-
duced. These new capabilities result inchangesin the drugdiscovery process. Forexample:
l Screeningforleadstructureschangedfromdirecttestinginliving systemstoinvitrohigh-throughputscreeningand
computational virtualscreening.
l Initialleads(hits)for optimizationchangedfromnaturalproductsandnaturalligandstocompounds fromlarge syn-
thetic librariesof diverse structures thatcover wide chemical space.
l Informationforcompounddesignwasenhancedfromstructure-activityrelationships(SAR)tox-raycrystallography,
nuclear magnetic resonance binding studies, andcomputational modeling.
l Lead optimization chemistry changedfrom one-at-a-time synthesis toparallel synthesis ofmultiple analogs.
l Traditional sequential experiments changed to parallel experiments, such as automated assays in microtiter plate
formats with robotics.
Drug discovery is constantly reevaluating itself in order to advance in speed, efficiency, and quality in order to remain
successful.
Pharmacokinetics(PK)andsafetyassessmentandoptimizationisanotherareaofdrugdiscoveryadvancement.Itoffers
significantopportunitiestoenhancedrugdiscoverysuccess.Thisbookfocusesonthefundamentalknowledge,methods,
andstrategiesforPKandsafety,andhowstructuresareoptimizedtoimprovetheseproperties.Thischapterdiscussesthe
benefits ofPK andsafety optimization.
2.2 DISCOVERY SCIENTISTS OPTIMIZE MANY PROPERTIES
There are many properties that affect PK and safety. Property liabilities often vary between different chemical series.
Examplesof properties of interest to discoveryscientists include the following:
l Structuralproperties
– Lipophilicity
– Topological polarsurface area
– Hydrogen bond acceptors and donors
– Ionization constant
– Molecularweight
– 3-Dimensional shape
– Reactivity
l Physicochemical properties
– Solubility
– Permeability
– Chemicalstability
l Biochemical properties
– Metabolic stability
– Transporters
Drug-LikeProperties.http://dx.doi.org/10.1016/B978-0-12-801076-1.00002-2
Copyright©2016ElsevierInc.Allrightsreserved. 5
Description:Of the thousands of novel compounds that a drug discovery project team invents and that bind to the therapeutic target, only a fraction have sufficient ADME (absorption, distribution, metabolism, elimination) properties, and acceptable toxicology properties, to become a drug product that will succes