TypesofDrugIsomers

Newmanpj

ChirallypureRitalinThalidomideisomersOmepgazole/PrilosecvsNexium

•  IsomersofdrugswillactDIFFERENTLY•  AbilityandHmingtointerconvertdependsontheenergybarrierandiscriHcalfordrugacHon

Chair/boat

Definingrotatablebonds•  DrugswithrotatablebondsundergoconformaHonalchanges

•  Rotatablebond:single,acyclic.•  Excludesinglebondstoaterminalatomorbondstolineargroups,e.g.CH3-C≡N.

•  HighlyrestrictedrotaHon,e.g.esterlinkages.

•  SinglebondsinsidecyclesmayundergoRESTRICTEDROTATION(ringpuckering)

Torsionangle

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

PopulaHonsofconformers

•  ThepopulaHonofdifferentconformersfollowsaBoltzmanndisribuHon

•  Consequencesfordrugbinding

•  UsingPiforentropycalculatons

•  UsingconformaHonalstrainEiintheenergybalancecalculaHonfordrugbinding

RTEE

j

iji

eNN −

−=

RTEE

j

iji

ePP −

−=

€

Sconf _ entropy = −R Pi lnstates∑ Pi

PosiHonalentropylossupondrugbinding:Entropyoffusion

•  TheentropylossuponcrystallizaHonfromtheliquidphasecanbeesHmatedasTΔS ~ 1.2-1.5 kcal/mol

•  enthalpyoffusion(melHng)forwater1.44,forethanol1.2

•  Asimilarentropylossisassociatedwiththedrugbinding

Mostdrugshaveionizablegroups

•  Fromabout55KdrugsinWDI,63%(~32K)areionizable.•  2/3rdshaveoneormorebasicgroup.

From:TimMitchellandRyszardKoblecki,MillenniumPharmaceuHcalsLtd.

E.g.:Carboxylicacid

E.g.:Amine

Acid⇔H+ +Base

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

VariabilityofDrugAcHon•  SolubilityandabsorpHonofadrugarehighlyvariableandrequireoppositeproperHes

•  Itdependsonthechemicalnatureofthedrug,pH,concentraHons

•  DissoluHon,absorpHonanddistribuHondependonthechargeofthedrug

•  Onlytheneutralformofadrugcanpassivelypermeatethemembrane

•  Everyexposedchargemagers(ratherthanthemean).Zwigerionsdonothelp

•  AcHvetransportmaychangethings:hijackingthebio-traffic

AbsorpHon•  TranscellulartransportisthemostcommonwayofdrugabsorpHonanddistribuHon

•  Small~100-550andnonpolarcompoundscangothroughthetranscellularroute(logP>0)

•  Thebiggesteffect:ioniza1on.Polarity:thesecond

Source:Drugdiscoverytoday

BloodBrainBarrier.Astrocytessurroundingcapillariesinthebrain.Transportispassive(PSA<75)ortransporter-mediated

Acidity,BodyandDrugs

•  Litmustest(pHindicator)•  Itisallaboutthesmallestnucleus,asingleproton

belowpH4.5 abovepH8.3 4.5 ↔ 8.3

Litmusisawater-solublemixtureofdifferentdyesextractedfromlichens.Chemicalstructureof7-hydroxyphenoxazone,thechromophoreoflitmuscomponents

Lichens:Fungus+Algaorcyanobacterium

Mostatomsstaycovalentlybonded,buthydrogenisanexcepHon

Hydrogenionsjump:•  Betweenwatermolecules•  Betweendrugsandwatermolecules•  Betweenbothandacids/basesinsoluHon

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)

+

DealingwithahugerangeofconcentraHons

Hydroxoniummolari1esrangefrom1to10-14M

Usethe“p”(power)operator:

p⇒−log10pH = −log10[H3

+O]

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

Self-ionizaHonofwater

•  2H2O→[OH-]+[H3O+]•  Kw=[H30+][OH-],dissociaHonconstantviamolariHesoftwoions.

•  Warning!DuetoaconvenHon,KwisNOTastandardequilibriumconstant,sincethe[H2O]2isomiged.WatermolaritywillalsobeomigedinKalater

•  Kw=10-14(mol/L)2

LowpH,highpH

•  pHofpurewater[H3O+]=[OH-]=c:•  Kw=c2,,

[H3O+]purew=10-7M

•  pH=7•  LowpHmanyions•  HighpHfewions

Acid-BaseImbalances

•  Acidosis– Highblood[H+]– LowbloodpH,<7.35

•  Alkalosis– Lowblood[H+]– HighbloodpH,>7.45

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

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( )

pH,pKaandlog10

Nowusethe“p”operator:

10-logp⇒a10a -logp KK =

↑⇒↓ donatingproton p aK

][-logp 310 OHH +=

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

Solubility•  Likedissolveslike•  Polarsolutesdissolveinpolarsolvents.

•  Nonpolarsolutesdissolveinnonpolarsolvents.

•  NeedtopredictormeasurepKa(s)sincechargedgroupshelpwatersolubilityandconflictwithfatsolubility.

µ 0aq + RT lnSW = µ 0s

From:LMLiu,A.LaioandA.MichaelidesPhys.Chem.Chem.Phys.,2011,13,13162

DrugSolubility•  Foreachdrug,waterandfatsolubilityvary.•  RelaHvesolubiliHesdependon

ChemicalstructureofthedrugpHofthesoluHonpKaofthedrug

•  SolubilitypercentagesdependonionizaHonraHos

AceHc-acid-dissociaHon

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

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

H.H.:aquanHtaHvepicture

•  Mostdrugsareweakacidsorweakbases

•  Itisnotallornothing,therearealwaysseveralspeciesatdifferentconcentraHons pKapH

BHB

pKapHHAA

−=⎟⎟⎠

⎞⎜⎜⎝

⎛

+

−=⎟⎟⎠

⎞⎜⎜⎝

⎛ −

][][log

][][log

FracHonIonizedasafuncHonofpKaandpH

+ -

0 0

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.

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-]

Amphotericdrugs

•  Ordinaryampholytes,e.g.m-aminophenol•  pKaacidic>pKabasic.pKaA=9.8,pKaB=4.4•  IncreasingpH:1.NH3+2.Neutral3.O-

Zwigerionicampholytes

•  E.g.Aminoacids,pepHdes

•  pKaacidic<pKabasic

DistribuHonofionicspeciesforthezwigerionicampholytelabetalol.fromA.Pagliara,P.-A.Carrupt,G.Caron,P.GaillardandB.Testa,Chem.Rev.,97,3385(1997).

IsoelectricPoint•  pI=pH=½(pKaacidic+pKabasic)•  ItcanbebothunchargedandzwigerionicormulHplycharged

•  ForabsorpHoneverychargecounts(notthetotalcharge)

•  pIisusedforisoelectricfocusing(Agarosegelelectrophoresis)

Zwigeriondrugs:Examples

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:

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

IonTrappingofanacidicdrug

Thesamehighlyfatsolubledrugreadilycrossesthestomachmembranesandentersbloodplasma,whichhasapHof7.5

pH–pKa=7.5–5.5=2[I]/[U]=102/1=100/1Forevery100moleculesofthedrugthatareionized,only1isunionized.Thedruginthebloodisnotveryfatsoluble.

Thisphenomenoniscallediontrapping.

AbsorpHonisquanHtaHvetoo

•  PermeaHonrate,RP=PAreaΔC•  Amountabsorbed=RP•Time

–  PismembraneparHHoncoefficient(relatedtoLogP)

–  AreaiseffecHvesurfaceareaofmembrane

–  ΔCisconcentraHondifferencefortheneutralformofthedrug

•  Astomach/Aileumdiffer1000Hmes.ThatmeansthatevenifthefracHonofneutralspeciesinstomachis100Hmesgreater,sHll10Hmesmorecompoundwillbeabsorbedinthegut.TheeffectofHmecomesontop.

Cout

Cin

A=120m2

A=0.1m2

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

+

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

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.

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

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