Page 1
TypesofDrugIsomers
Newmanpj
ChirallypureRitalinThalidomideisomersOmepgazole/PrilosecvsNexium
• IsomersofdrugswillactDIFFERENTLY• AbilityandHmingtointerconvertdependsontheenergybarrierandiscriHcalfordrugacHon
Chair/boat
Page 2
Definingrotatablebonds• DrugswithrotatablebondsundergoconformaHonalchanges
• Rotatablebond:single,acyclic.• Excludesinglebondstoaterminalatomorbondstolineargroups,e.g.CH3-C≡N.
• HighlyrestrictedrotaHon,e.g.esterlinkages.
• SinglebondsinsidecyclesmayundergoRESTRICTEDROTATION(ringpuckering)
Torsionangle
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ConformaHonalEntropyLossassociatedwithtargetbinding
• UponbindinglosesmostofitsrotamersandonlytheonecompaHblewiththebindingsiteischosen,italsolosestranslaHonalandrotaHonalDFs
• Fullmethod:definealllowenergystatesandassignPi,
• SimplemethodforcounHngrotamers:3perbond:3x3x3…
• SimpleandadvancedentropicesHmates
• RealcounHngneedstoincludeenergy(clashing)andprobabilityesHmates
torsionsNrotN 3∝
Sconf _ entropy = R ln3Ntor = RNtor ln3 ≈ RNtor
Gconf _ entropy ≈ −RTNtor ≈ −0.6Ntor[kcal /mol]
Sconf _ entropy = −R Pi lntorsions∑ Pi
Smoleculeconf _ entropy = kB ln(NstatesIn1molecule )
Smoleconf _ entropy = R ln(NstatesIn1molecule ) =
−R ln(1 / N ) = −R (1 / N )N∑ ln(1 / N )
Smoleconf _ entropy = −R Pi lnstates∑ Pi
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PopulaHonsofconformers
• ThepopulaHonofdifferentconformersfollowsaBoltzmanndisribuHon
• Consequencesfordrugbinding
• UsingPiforentropycalculatons
• UsingconformaHonalstrainEiintheenergybalancecalculaHonfordrugbinding
RTEE
j
iji
eNN −
−=
RTEE
j
iji
ePP −
−=
€
Sconf _ entropy = −R Pi lnstates∑ Pi
Page 5
PosiHonalentropylossupondrugbinding:Entropyoffusion
• TheentropylossuponcrystallizaHonfromtheliquidphasecanbeesHmatedasTΔS ~ 1.2-1.5 kcal/mol
• enthalpyoffusion(melHng)forwater1.44,forethanol1.2
• Asimilarentropylossisassociatedwiththedrugbinding
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Mostdrugshaveionizablegroups
• Fromabout55KdrugsinWDI,63%(~32K)areionizable.• 2/3rdshaveoneormorebasicgroup.
From:TimMitchellandRyszardKoblecki,MillenniumPharmaceuHcalsLtd.
E.g.:Carboxylicacid
E.g.:Amine
Acid⇔H+ +Base
Page 7
AminesinDrugs:Examples
• Chlorpheniramine:ananHhistamine.• Chlorpromazine:atranquillizer• Ephedrineandphenylephrine:decongestants.• Amphetamine,methamphetamine,andmethcathinone:
psychosHmulantamines• Amitriptyline,imipramine,lofepramineandclomipramine:
tert.amines,tricyclicsad.• Nortriptyline,desipramine,andamoxapine:secondary
amines,tricyclicanHdepressants
LonepairorH+dependingonthepH
Page 8
VariabilityofDrugAcHon• SolubilityandabsorpHonofadrugarehighlyvariableandrequireoppositeproperHes
• Itdependsonthechemicalnatureofthedrug,pH,concentraHons
• DissoluHon,absorpHonanddistribuHondependonthechargeofthedrug
• Onlytheneutralformofadrugcanpassivelypermeatethemembrane
• Everyexposedchargemagers(ratherthanthemean).Zwigerionsdonothelp
• AcHvetransportmaychangethings:hijackingthebio-traffic
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AbsorpHon• TranscellulartransportisthemostcommonwayofdrugabsorpHonanddistribuHon
• Small~100-550andnonpolarcompoundscangothroughthetranscellularroute(logP>0)
• Thebiggesteffect:ioniza1on.Polarity:thesecond
Source:Drugdiscoverytoday
BloodBrainBarrier.Astrocytessurroundingcapillariesinthebrain.Transportispassive(PSA<75)ortransporter-mediated
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Acidity,BodyandDrugs
• Litmustest(pHindicator)• Itisallaboutthesmallestnucleus,asingleproton
belowpH4.5 abovepH8.3 4.5 ↔ 8.3
Litmusisawater-solublemixtureofdifferentdyesextractedfromlichens.Chemicalstructureof7-hydroxyphenoxazone,thechromophoreoflitmuscomponents
Lichens:Fungus+Algaorcyanobacterium
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Mostatomsstaycovalentlybonded,buthydrogenisanexcepHon
Hydrogenionsjump:• Betweenwatermolecules• Betweendrugsandwatermolecules• Betweenbothandacids/basesinsoluHon
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Acid-BaseBalance• NormalmetabolismproducesH+,(acidity)• DissociaHonofwater:2H2O→[OH-]+[H3O+],i.e.hydroxide+hydro[xo]niumions
• High[H+]isacidic,low[H+]isbasic• ThreeHomeostaHcmechanisms:– Buffersystems,-instantaneous;temporary– ExhalaHonofCO2-operateswithinminutes;cannotcompletelycorrectseriousimbalances
– KidneyexcreHon-cancompletelycorrectanyimbalance(eventually)
+
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DealingwithahugerangeofconcentraHons
Hydroxoniummolari1esrangefrom1to10-14M
Usethe“p”(power)operator:
p⇒−log10pH = −log10[H3
+O]
Page 14
pH• pH(powerofHydrogenion)isameasureof[H3O+]molarity.
• pH≡−log10[aH+],• aH+isacHvityofwater• aH+≈[H+],i.e.molarityofhydroxoniumions,inM=mol/L
• Example:lemonadehas[H+]~0.005M,pH≈-log10(0.005)≈2.3
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Self-ionizaHonofwater
• 2H2O→[OH-]+[H3O+]• Kw=[H30+][OH-],dissociaHonconstantviamolariHesoftwoions.
• Warning!DuetoaconvenHon,KwisNOTastandardequilibriumconstant,sincethe[H2O]2isomiged.WatermolaritywillalsobeomigedinKalater
• Kw=10-14(mol/L)2
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LowpH,highpH
• pHofpurewater[H3O+]=[OH-]=c:• Kw=c2,,
[H3O+]purew=10-7M
• pH=7• LowpHmanyions• HighpHfewions
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Acid-BaseImbalances
• Acidosis– Highblood[H+]– LowbloodpH,<7.35
• Alkalosis– Lowblood[H+]– HighbloodpH,>7.45
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AbsorpHoninGItract
Stomach
1.4-2.1
3-7
Ileum
6.8-8.0
6.8-8.0
Colon
5-8
5-8
fastedstate
fedstate
Jejunum 4.4-6.65.2-6.2
0.1m2
0.3m2
Dressman,Amidon,Reppas,Shah,Pharm.Res.1998,15,11.
0.5-3.5hr 3-4hr
1-3d
120m2
acids bases
pH
Page 19
AcidsandBases
We’llconsideronlyBronstedequilibria.E.g.,
or,moregenerally,whichhastheacidityconstantKa([H2O]isomiged,asinKw)
-32 AcOHOH HAc +⇔+ +
€
NH4+ + H2O⇔ H3O
+ + NH3
BaseOHOH Acid 32 +⇔+ +
€
Ka =a H3O
+( )a Base( )a Acid( )
Page 20
pH,pKaandlog10
Nowusethe“p”operator:
10-logp⇒a10a -logp KK =
↑⇒↓ donatingproton p aK
][-logp 310 OHH +=
Page 21
pKaofsomefuncHonalgroups
phosphates(DNA)1.5,6.5purineN(DNA)9pyrimidineN(DNA)9carboxylates(a.a.,asp,glu,C-ter)3.5-5phenols(a.a.,tyr)9.5-11sul}ydryls(a.a.,cys)8.5hydroxyls(a.a.,ser,thr)13.5amines(DNA,ade,cyt)3.5-4imidazole(a.a.,his)6.5-7amino(a.a,lys,N-terminus)10guanidinium(a.a.,arg)13
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Solubility• Likedissolveslike• Polarsolutesdissolveinpolarsolvents.
• Nonpolarsolutesdissolveinnonpolarsolvents.
• NeedtopredictormeasurepKa(s)sincechargedgroupshelpwatersolubilityandconflictwithfatsolubility.
µ 0aq + RT lnSW = µ 0s
From:LMLiu,A.LaioandA.MichaelidesPhys.Chem.Chem.Phys.,2011,13,13162
Page 23
DrugSolubility• Foreachdrug,waterandfatsolubilityvary.• RelaHvesolubiliHesdependon
ChemicalstructureofthedrugpHofthesoluHonpKaofthedrug
• SolubilitypercentagesdependonionizaHonraHos
AceHc-acid-dissociaHon
Page 24
SolubilityandpKa
DrugpKa Solu1onpH
<7(AcidicsoluHon) >7(BasicsoluHon)
<7(Acidicdrug,chargeis-1or0)
pKa>pHUn-ionized,Fatsoluble
pKa<pH(-)Ionized,Watersoluble
>7(Basicdrug,chargeis0or+1)
pKa>pH(+)Ionized,Watersoluble
pKa<pH(0)Un-ionized,Fatsoluble
[H+]Excess [H+]Deficiency
CauHon:InmostinformaHonsourcesanddatabasesthedruggroupsionizedatpH=7.4groupswillsHllbeshownasneutral.
Norepinephrineinitsunnaturalneutralform
Page 25
Henderson-Hasselbalch• ThedifferencebetweenthepHofthesoluHonandthepKaofthedrugisthecommonlogarithmoftheraHoofionizedtounionizedformsofthedrug.
• ForaciddrugsLog(Ionized/Unionized)=pH-pKa,or[I]/[U]=10(pH-pKa) Deriva1on:
Ka=[H+][A-]/[HA]-logKa=-log([H+][A-]/[HA])-logKa=-log[H+]-log([A-]/[HA])pKa=pH-log([A-]/[HA])log([A-]/[HA])=pH-pKa
Page 26
H.H.:aquanHtaHvepicture
• Mostdrugsareweakacidsorweakbases
• Itisnotallornothing,therearealwaysseveralspeciesatdifferentconcentraHons pKapH
BHB
pKapHHAA
−=⎟⎟⎠
⎞⎜⎜⎝
⎛
+
−=⎟⎟⎠
⎞⎜⎜⎝
⎛ −
][][log
][][log
Page 27
FracHonIonizedasafuncHonofpKaandpH
+ -
0 0
Page 28
Weakacidismostlyneutralinstomach
Adrugisaweakacid,hasapKaof5.5.Takenorally,itisinastomachsoluHonofpH3.5.
pH–pKa=3.5–5.5=-2Foranacid,weuse:ionized/unionized=10-2/1=1/100
Forevery1moleculeofthedrugthatisionized,100areunionized.Thisdruginthestomachishighlyfatsoluble.
Page 29
BasicDrugsForbasicdrugs,everythingisthe
sameexceptthatthera=oreverses:
Log(Unionized/Ionized)=pH–pKa
Examples:Chlorpheniramine,chlorpromazine,ephedrineandphenylephrine,amphetamine,methamphetamine,andmethcathinone,amitriptyline,imipramine,lofepramineandclomipramine,nortriptyline,desipramine,andamoxapine.
pKapHBHB
pKapHHAA
−=⎟⎟⎠
⎞⎜⎜⎝
⎛
+
−=⎟⎟⎠
⎞⎜⎜⎝
⎛ −
][][log
][][log
NH2+[Cl-]
Page 30
Amphotericdrugs
• Ordinaryampholytes,e.g.m-aminophenol• pKaacidic>pKabasic.pKaA=9.8,pKaB=4.4• IncreasingpH:1.NH3+2.Neutral3.O-
Page 31
Zwigerionicampholytes
• E.g.Aminoacids,pepHdes
• pKaacidic<pKabasic
DistribuHonofionicspeciesforthezwigerionicampholytelabetalol.fromA.Pagliara,P.-A.Carrupt,G.Caron,P.GaillardandB.Testa,Chem.Rev.,97,3385(1997).
Page 32
IsoelectricPoint• pI=pH=½(pKaacidic+pKabasic)• ItcanbebothunchargedandzwigerionicormulHplycharged
• ForabsorpHoneverychargecounts(notthetotalcharge)
• pIisusedforisoelectricfocusing(Agarosegelelectrophoresis)
Page 33
Zwigeriondrugs:Examples
Page 34
CalculaHonofthepHofdrugsoluHons
• ThedrugsoluHonitselfcandevelopitsownpH
• ThepHcanbederivedfromitspKaandconcentraHon,C
Aweaklyacidicdrug:HA+H2O=[A-]+[H30+](1-a)cacaca–degreeofdissociaHon
a<<1ac=[H+]atc>≈10-7M
Note:thisapproxima=on
breaksatinfinitesimalconcentra=ons.
cpKpH a log21
21 −=
Ka =a2c2
(1− a)c≈ a2c
a2 = Ka / ca2c2 = Kac
[H+]= (Kac)12
− log([H+]) = − log((Kac)12 )
− log([H+]) = − log(Ka )− log(c)12
Deriva1on:
Forthesolu1onofaweaklyacidicdrug:
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Weaklybasicdrugs• Similarlyitcanbeshownthat
• Example:codeinemonohydrate(317.4),pKa=8.2
C=0.026MpH=7+4.1-0.79
cpKpHcpKpKpH
a
aw
log7log
21
21
21
21
21
++=
++=
BasicAmineischargedatneutralpH
Page 36
IonTrappingofanacidicdrug
Thesamehighlyfatsolubledrugreadilycrossesthestomachmembranesandentersbloodplasma,whichhasapHof7.5
pH–pKa=7.5–5.5=2[I]/[U]=102/1=100/1Forevery100moleculesofthedrugthatareionized,only1isunionized.Thedruginthebloodisnotveryfatsoluble.
Thisphenomenoniscallediontrapping.
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AbsorpHonisquanHtaHvetoo
• PermeaHonrate,RP=PAreaΔC• Amountabsorbed=RP•Time
– PismembraneparHHoncoefficient(relatedtoLogP)
– AreaiseffecHvesurfaceareaofmembrane
– ΔCisconcentraHondifferencefortheneutralformofthedrug
• Astomach/Aileumdiffer1000Hmes.ThatmeansthatevenifthefracHonofneutralspeciesinstomachis100Hmesgreater,sHll10Hmesmorecompoundwillbeabsorbedinthegut.TheeffectofHmecomesontop.
Cout
Cin
A=120m2
A=0.1m2
Page 38
DrugSalts:Bases
Note:HydrochlorideinDrug.HClmaybemisleading,itshouldbejustchloride(Drug+.[Cl-]),samewithH2SO4
Acid[AH]
BasicDrug[B] + -
Drug,BH+Anion
AnionicSaltoftheDrug
plus
Acid Anion Examples
Hydrochloride(HCl) Cl- PyridoxineHCl,PramipexoleHClChlorpromazineHCl,Demeclocycline..DemethylchlortetracyclineNalbuphine,ChlorhexidinePropafenone,MitoxantroneLincomycin,RoHgoHneVilazodone,Naphazoline
SulfuricAcid SO42- Dextroamphetamine,Hydroxychloroquine
AceHcAcid(acetate) CH3COO- Leuprolide,Goserelin,Desmopressin,…
cocainehydrochloride
+
Page 39
DrugSalts:AcidsBaseB,e.g.NaOH
AcidicDrugAH
e.g.R-COOH - +Drug
ion,[A-] CaHon
CaHonicSaltoftheDrug
plus
OH-Base Ca1on Examples
Sodium Na+ Ecabet,Diclofenac,Indomethacin,Benzoate,Salicylate
Calcium Ca++ AtorvastaHn,CalciumGluceptate
Potassium K+ PenicillinVPotassium,Losartan
Ca++needstwonegaHvecharges
CalciumGluceptate
Warning:donotforgettousecorrectmolecularweightofthesalt
Page 40
Salts:summary• Stoichiometry:makesure
thatthetotalformalchargeiszero(e.g.[D-]2Me2+)
• AmbiguityofchemicalrepresentaHon:[DH+][Cl-]vs[D][HCL],MolWeight.
• Solubilityofcrystals:usuallybegerthannon-salt,butdiffersbetweendifferentsalts.
• Iden=calinSolu=on:OncethesaltisdissolveditbecomesidenHcaltothenon-saltformofthedruginsoluHon
• Resonance:Example,sulfate:perfecttetrahedronwithtotalnegaHvechargeof-2distributedbetween4negaHveoxygensandoneposiHvessulfur.
Page 41
Saltswithbegersolubility:example• Example:
– Phenobarbital,awhitepowder,isaweakacidwithlimitedsolubilityinwater,
– thesodiumsaltofPhenobarbital,alsoawhitepowder,thesaltoftheweakacid,nowwatersoluble
• pKa=7.41
• pH(satur.sol)5~10.• Solubility:1g/L1g/10mL
Epoprostenol.Na+ProstacyclinI.V.vasodilatorinischemia&PH
Na+
Moreexamples:Naproxen NaproxenSodiumFenoprofen FenoprofenCalciumPenicillinG PenicillinGPotassium
Page 42
Moreanionsforbasicdrugs• Base Salt/ConjugateAcid• Diphenhydramine DiphenhydramineHCL• Glucosamine Glucosaminesulfate• Epinephrine Epinephrinesulfate• Ephedrine EphedrineHCl• Atropine Atropinesulfate• Tetracycline TetracyclineHCl
• Mostofthesedrugs,asyoucantellbytheirname,are"amines",whichmeanstheyareweakbases
• AcetateCH3COO−(aceHcacid)• CarbonateCO3
2−,carbonicacid)• ChlorideCl−(hydrochloricacid)• CitrateHOC(COO−)(CH2COO−)2(citricacid)• CyanideC≡N−(hydrocyanicacid)(toxic)• NitrateNO3
−(nitricacid)• NitriteNO2
−(nitrousacid)• PhosphatePO4
3−(phosphoricacid)• SulfateSO4
2−(sulfuricacid)Sodium-nitroprusside,-vasodilator