Alzheimer's Disease

187 Pages·2008·3.5 MB·English

by  Lit-Fui Lau

2
Topics in Medicinal Chemistry
EditorialBoard:
P.R.Bernstein·A.Buschauer·J.A.Lowe·H.U.Stilz
Alzheimer’s Disease
Volume Editors: Lit-Fui Lau· Michael A. Brodney
Withcontributionsby
S.Berg·R.V.Bhat·M.A.Brodney·J.Burrows·A.I.Bush
G.Grossberg·L.-F.Lau·J.Lindquist·Q.Jiang·J.Kao·G.Landreth
S.Mandrekar·H.D.Soares·D.L.Sparks·A.R.White
123
Drugresearchrequiresinterdisciplinaryteam-workattheinterfacebetweenchemistry,biologyand
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biology,drugabilityoftargets,drugdesignapproaches,chemogenomics,syntheticchemistryinclud-
ingcombinatorialmethods,bioorganicchemistry,naturalcompounds,high-throughputscreening,
pharmacologicalinvitroandinvivoinvestigations,drug-receptorinteractionsonthemolecularlevel,
structure-activityrelationships,drugabsorption,distribution, metabolism,elimination, toxicology
andpharmacogenomics.
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LibraryofCongressControlNumber:2007935106
ISSN1862-2461
ISBN978-3-540-74228-9SpringerBerlinHeidelbergNewYork
DOI10.1007/978-3-540-74229-6
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VolumeEditors
Dr.Lit-FuiLau Dr.MichaelA.Brodney
CNSDiscovery CNSDiscovery
PfizerGlobalResearch&Development PfizerGlobalResearch&Development
Groton,CT06340 Groton,CT06340
USA USA
lit-fui.lau@pfizer.com michael.a.brodney@pfizer.com
EditorialBoard
Dr.PeterR.Bernstein Prof.JohnA.Lowe
AstraZenecaPharmaceuticals PfizerInc.
1800ConcordPike MS8220-4118
FairfaxResearchCenterB313 EasternPointRoad
POBox15437 Groton,CT06340
Wilmington,DE19850-5437 USA
USA
Dr.HansUlrichStilz
Prof.Dr.ArminBuschauer
AventisPharmaDeutschlandGmbH
Inst.f.Pharmazie Geb.G838
UniversitätRegensburg 65926Frankfurta.M.
Universitätsstr.31
93053Regensburg
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PrefacetotheSeries
Medicinalchemistryisbothscienceandart.Thescienceofmedicinalchemistry
offersmankindoneofitsbesthopesforimprovingthequalityoflife.Theart
ofmedicinalchemistrycontinuestochallengeitspractitionerswiththeneed
for both intuition and experience to discover new drugs. Hence sharing the
experience of drug discovery is uniquely beneficial to the field of medicinal
chemistry.
The series Topics in Medicinal Chemistry is designed to help both novice
and experienced medicinal chemists share insights fromthe drug discovery
process. For the novice, the introductory chapter to each volume provides
background and valuable perspective on a field of medicinal chemistry not
availableelsewhere.Succeeding chaptersthenprovideexamplesofsuccessful
drugdiscoveryeffortsthatdescribethemostup-to-dateworkfromthisfield.
Theeditorshavechosentopicsfrombothimportanttherapeuticareasand
from work that advances the discipline of medicinal chemistry. For exam-
ple, cancer, metabolic syndrome and Alzheimer’s disease are fields in which
academiaandindustryareheavilyinvestedtodiscovernewdrugsbecauseof
theirconsiderableunmetmedicalneed.Theeditorshavethereforeprioritized
coveringnewdevelopmentsinmedicinalchemistryinthesefields.Inaddition,
importantadvancesinthediscipline,suchasfragment-baseddrugdesignand
otheraspectsofnewlead-seeking approaches,arealsoplannedforearlyvol-
umesinthisseries.Eachvolumethusoffersauniqueopportunitytocapture
themostup-to-dateperspectiveinanareaofmedicinalchemistry.
Dr.PeterR.Bernstein
Prof.Dr.ArminBuschauer
Dr.JohnLowe
Dr.HansUlrichStilz
PrefacetoVolume2
ItwasonehundredandoneyearsagothatAloisAlzheimerpresentedatasci-
entificmeetingacaseofprogressivedementiaina51-year-oldpatientAuguste
D.Postmortemanalysisrevealedtwopathologies,namely,senileplaquesand
neurofibrillary tangles. These findings were published the following year in
1907. In 1910 Emil Kraepelin, Alzheimer’s mentor, named this disease after
its discoverer. The two initial pathological findings remain the postmortem
diagnostic features of Alzheimer’s disease (AD) today. At the time, however,
KraepelinmadethedistinctionbetweenADandsenile dementia(> 65years
old)despite their similarities inpathologiesandclinicalsymptoms [1, 2]. In
1976 Robert Katzman argued in an editorial in the April issue of Archives
of Neurology that this distinction be removed. AD has thus morphed from
arareorphandisease toonewithamuchbigger socioeconomicthreat. This
nosologicalshifthasbroughtADintothelimelightandexponentially—and
thankfully—hastenedthepaceofresearch.Enormousstrideshavebeenmade
inunderstandingtherootcausesandriskfactorsofthedisease.Analogousto
thediscoveryofnewcancertreatmentsoverthepast20years(seeVolume1),
advances in understanding the underlying molecular biology are providing
novel drug targets for future research. These efforts have resulted in greater
than 500 ongoing clinical trials focused onnovel mechanisms and interven-
tionpointsinthedisease.Thesetrialswillhopefullyleadtothefirstapproval
ofadisease-modifying agent forAD andpave theway foranarsenal ofnew
medications.
October,2007,Groton Lit-FuiLauandMichaelA.Brodney
Connecticut,USA
1.BallengerJF(2006)JAlzheimersDis9:5
2.LageJM(2006)JAlzheimersDis9:15
Contents
TherapeuticApproachesfortheTreatmentofAlzheimer’sDisease:
AnOverview
L.-F.Lau·M.A.Brodney . . . . . . . . . . . . . . . . . . . . . . . . . . 1
CholinesteraseInhibitors
J.Kao·G.Grossberg . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
BeyondCholesterol:StatinBenefitsinAlzheimer’sDisease
H.D.Soares·D.L.Sparks . . . . . . . . . . . . . . . . . . . . . . . . . 53
PPARγ AgonistsfortheTreatmentofAlzheimer’sDisease
Q.Jiang·S.Mandrekar·G.Landreth . . . . . . . . . . . . . . . . . . . 81
MetalComplexingAgentsfortheTreatmentofAlzheimer’sDisease
A.R.White·A.I.Bush . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
GSK-3InhibitorsfortheTreatmentofAlzheimer’sDisease
R.V.Bhat·S.Berg·J.Burrows·J.Lindquist . . . . . . . . . . . . . . . 137
AuthorIndexVolumes1–2 . . . . . . . . . . . . . . . . . . . . . . . . . 175
SubjectIndex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
TopMedChem(2008)2:1–24
DOI10.1007/7355_2007_017
© Springer-VerlagBerlinHeidelberg
Publishedonline:30November2007
TherapeuticApproaches
fortheTreatmentofAlzheimer’sDisease:AnOverview
Lit-FuiLau((cid:1))·MichaelA.Brodney((cid:1))
CNSDiscovery,PfizerGlobalResearchandDevelopment,Groton,CT06340,USA
Lit-fui.lau@pfizer.com,Michael.a.brodney@pfizer.com
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 ADSymptomsandNeutodegeneration . . . . . . . . . . . . . . . . . . . . 3
3 PathologicalFeaturesofAD . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.1 AmyloidPathologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
3.2 TauPathologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.3 Microgliosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4 EtiologyandEnvironmentalRiskFactorsforAD . . . . . . . . . . . . . . 6
5 TherapeuticStrategiesandApproachesfortheTreatmentofAD. . . . . . 8
5.1 GeneralStrategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5.2 SpecificApproaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.2.1 TargetingSymptoms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.2.2 TargetingAmyloidPathologies . . . . . . . . . . . . . . . . . . . . . . . . . 11
5.2.3 TargetingTauPathologies. . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
5.2.4 TargetingMicrogliosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
5.2.5 TargetingMultipleFunctionalandPathologicalDeficits . . . . . . . . . . . 15
6 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Abstract Alzheimer’sdisease(AD)isaneurodegenerativediseasethatrobsthemindsof
our elderly population. Approximatelyone in every eight adultsover the age of 65 and
nearlyhalfofthoseover85areafflictedwiththisdisease.Agingandotherriskfactors(e.g.
cardiovasculardiseases,obesityanddiabetes)indevelopedsocietieswillimposeaneverin-
creasingsocioeconomicthreatinthefuture.CurrentmedicinesforADpatientsaremainly
symptomatictreatmentsandahugeunmetmedicalneedexiststoslow,stoporreversethe
progressionofthisdisease.Agreatdealofresearchhasbeendedicatedtounderstanding
thepathogenesisofADfromwhichcomemanyideasfor interveninginitsprogression.
They canbe grossly categorizedinto those targetingthe amyloidpathology,tau pathol-
ogy, microgliosis(neuroinflammation)andfunctionaldeficits. Someof theseideashave
beenfast-trackedtoclinicaltrialsduetotheavailabilityofmedicineswithprovenclinical
efficaciesforotherdiseaseswhileothersrepresentnovelchemicalentities.Ourcontinued
commitmentinsearchingforefficacioustreatmentstogetherwithahealthierlifestylewill
beimportantinfightingagainstthegrowingthreatofthisdeterioratingdisease.
Keywords Aβ·Alzheimer’sdisease·Amyloid·Microgliosis·Neurodegeneration·tau