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Structure-activity relationships

Structure-activity relationships. Structure – activity relationship (SAR)

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Structure-activity relationships

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  1. Structure-activityrelationships

  2. Structure–activityrelationship (SAR) Structure–activityrelationshipstudiesareusuallycarriedoutbymakingminorchangestothestructure of a leadtoproduceanaloguesandassessingtheeffectthatthesestructuralchangeshave on biologicalactivity. Theinvestigation of numerousleadcompoundsandtheiranalogues has made it possibletomakesomebroadgeneralisationsaboutthebiologicaleffects of specifictypes of structuralchanges.

  3. Thesechangesmay be convenientlyclassified as changing: • the size andshape of thecarbonskeleton • thenatureanddegree of substitution • thestereochemistry of thelead

  4. Changing size andshape • Theshapesandsizes of molecules can be modified in a variety of ways, such as: • changingthenumber of methylenegroups in chainsandrings • increasingordecreasingthedegree of unsaturation • introducingorremoving a ring system

  5. Changingthenumber of methylenegroups in chainsandrings Increasingthenumber of methylenegroupsin a chainor ring increasesthe size andthelipophilicity of thecompound. It is believedthatanyincrease in activitywithincrease in thenumber of methylenegroups is probablydueto an increase in thelipidsolubility of theanalogue, whichgives a bettermembranepenetration. Conversely, a decrease in activitywith an increase in thenumber of methylenegroups is attributedto a reduction in thewatersolubility of theanalogues. Thisreduction in watersolubility can result in thepoordistribution of theanalogue in theaqueousmedia as well as thetrapping of theanalogue in biologicalmembranes.

  6. Introducingchainbranching, differentsizedringsandthesubstitution of chainsforrings, andviceversa, mayalsohave an effect on thepotencyandtype of activity of analogues. Forexample, thereplacement of thesulphur atom of theantipsychoticchlorpromazineby -CH2-CH2- producesthe anti depressantclomipramine.

  7. Changingthedegree of unsaturation Theremoval of doublebondsincreasesthedegree of flexibility of themolecule, whichmaymake it easierfortheanalogueto fit intoactiveandreceptorsitesbytakingup a moresuitableconformation. However, an increase in flexibilitycouldalsoresult in a changeorloss of activity. Theintroduction of a doublebondincreasestherigidity of thestructure. Itmayalsointroducethecomplication of E and Z isomers, whichcouldhavequitedifferentactivities.Theanaloguesproducedbytheintroduction of unsaturatedstructuresinto a leadcompoundmayexhibitdifferentdegrees of potencyordifferenttypes of activities.

  8. Forexample, thepotency of prednisone is about 30 timesgreaterthanthat of itsparentcompoundcortisol, whichdoes not have a 1–2 C=C bond. Thereplacement of the S atom of theantipsychoticphenothiazinedrugsby a –CH=CH- groupgivestheantidepressantdibenzazepinedrugs, such as protriptyline.

  9. Theintroduction of a C=C groupwilloftengiveanaloguesthataremoresensitivetometabolicoxidation. Thismayormay not be a desirablefeatureforthenewdrug. Furthermore, thereactivity of theC=C frequentlycausestheanalogueto be moretoxicthanthelead.

  10. Introductionorremoval of a ring system Theintroduction of a ring systemchangestheshapeandincreasestheoverall size of theanalogue. Theeffect of thesechanges on thepotencyandactivity of theanalogue is not generallypredictable. However, theincrease in size can be useful in filling a hydrophobicpocket in a target site, whichmightstrengthenthebinding of thedrugtothetarget.

  11. Forexample, it has beenpostulatedthattheincreasedinhibitoryactivity of thecyclopentylanalogue (rolipram) of 3-(3,4-dimethyloxyphenyl)-butyrolactamtowardscAMPphosphodiesterase is duetothecyclopentylgroupfilling a hydrophobicpocket in theactive site of thisenzyme.

  12. Theincorporation of smaller, as againstlarger, alicyclic ring systemsinto a leadstructurereducesthepossibility of producing an analoguethat is toobigforitstarget site. Italsoreducesthepossibility of complicationscausedbytheexistence of conformers. However, theselection of thesystemfor a particularanaloguemaydepend on theobjective of thealteration. Forexample, theantidepressanttranylcypromine is morestablethanitsanalogue 1-amino-2-phenylethene.

  13. Theinsertion of aromaticsystemsintothestructure of theleadwillintroducerigidityintothestructure as well as increasethe size of theanalogue. Thelattermeansthatsmallaromaticsystemssuch as benzene andfive-memberedheterocyclicsystemsareoftenpreferredtolargersystems. However, thep electrons of aromaticsystemsmayormay not improvethebinding of theanaloguetoitstarget site. Furthermore, heterocyclicaromaticsystemswillalsointroduceextrafunctionalgroupsintothestructure, whichcouldalsoaffectthepotencyandactivity of theanalogue.

  14. Forexample, thereplacement of the N-dimethylgroup of chlorpromazineby an N-methylpiperazinegroupproduces an analogue (prochlorperazine) withincreasedantiemeticpotency but reducedneurolepticactivity. It has beensuggestedthatthischange in activitycould be duetothe presence of theextratertiary amine group.

  15. Theincorporation of ring systems, especiallylargersystems, intothestructure of a lead can be usedtoproduceanaloguesthatareresistanttoenzymicattackbystericallyhinderingtheaccess of theenzymetotherelevantfunctionalgroup.

  16. Forexample, theresistance of diphenicillinto-lactamase is believedto be duetothediphenylgrouppreventingtheenzymefromreachingthe-lactam. It is interestingtonotethat 2-phenylbenzylpenicillin is not resistantto-lactamaseattack. Inthiscase, it appearsthatthediphenylgroup is too far awayfromthe-lactam ring tohindertheattack of the--lactamase.

  17. Introduction of newsubstituents Theformation of analoguesbytheintroduction of newsubstituentsintothestructure of a leadmayresult in an analoguewithsignificantlydifferentchemicalandhencedifferentpharmacokineticproperties. Forexample, theintroduction of a newsubstituentmaycausesignificantchanges in lipophilicity, whichaffect transport of theanaloguethroughmembranesandthevariousfluidsfound in the body. Itwouldalsochangetheshape, whichcouldresult in conformationalrestrictionsthataffectthebindingtotarget site. Inadditionthe presence of a newgroupmayintroduce a newmetabolicpathwayfortheanalogue. Thesechangeswill in turnaffectthepharmacodynamicpropertiesof theanalogue.

  18. Forexample, theycouldresult in an analoguewitheitherincreasedordecreasedpotencyduration of action, metabolicstabilityandunwantedsideeffects. Thechoice of substituentwilldepend on thepropertiesthatthedevelopmentteamdecidetoenhance in an attempttomeettheirobjectives. Eachsubstituentwillimpartitsowncharacteristicpropertiestotheanalogue. However, it is possibletogeneraliseabouttheeffect of introducing a newsubstituentgroupinto a structure but therewill be numerousexceptionstothepredictions.

  19. Methylgroups Theintroduction of methylgroupsusuallyincreasesthelipophilicityof thecompoundandreducesitswatersolubility as shownby an increase in thevalue of thepartitioncoefficient (Table). Itshouldimprovetheease of absorption of theanalogueinto a biologicalmembrane but willmakeitsreleasefrombiologicalmembranesintoaqueousmediamoredifficult. Theintroduction of a methylgroupmayalsoimprovethebinding of a ligandtoitsreceptorbyfilling a pocket on thetarget site.

  20. TableThechange in thepartitioncoefficients (P) of somecommoncompoundswhenmethylgroupsareintroducedintotheirstructures. Thegreaterthevalue of P themorelipidsolublethecompound. Benzene andtoluenevaluesweremeasuredusing an n-octanol/watersystemwhilsttheremainingvaluesweremeasuredusing an oliveoil/watersystem.

  21. Theincorporation of a methylgroupcan imposestericrestrictionson thestructure of an analogue.

  22. Forexample, theortho-methylanalogue of diphenhydramineexhibitsnoantihistamineactivity. Harmes et al. suggestthisto be duetotheortho-methylgrouprestrictingrotationaboutthe C–O bond of thesidechain. Thispreventsthemoleculeadoptingtheconformationnecessaryforantihistamineactivity. It is interestingtonotethatthe para-methylanalogue is 3.7 timesmoreactivethandiphenhydramine

  23. Theincorporation of a methylgroupcan haveone of three general effects on the rate of metabolism of an analogue. Itcan result in either an increased rate of metabolismduetooxidation of themethylgroup, (2) an increase in the rate of metabolismduetodemethylationbythe transfer of themethylgrouptoanothercompound or (3) a reduction in the rate of metabolismof theanalogue.

  24. 1. A methylgroupboundto an aromatic ring or a structuremay be metabolisedto a carboxylicacid, which can be moreeasilyexcreted. Forexample, theantidiabetictolbutamide is metabolisedtoitslesstoxicbenzoicacidderivative. Theintroduction of a reactive C–CH3 groupoffers a detoxificationrouteforleadcompoundsthataretootoxicto be of use.

  25. 2. Demethylation is morelikelytooccurwhenthemethylgroup is attachedtopositivelychargednitrogenandsulphuratoms, although it is possibleforanymethylgroupattachedto a nitrogen, oxygenorsulphur atom toact in thismanner. A number of methyltransfershavebeenassociatedwithcarcinogenicaction. 3. Methylgroups can reducethe rate of metabolism of a compoundbymasking a metabolicallyactivegroup, therebygivingtheanalogue a slower rate of metabolismthanthelead.

  26. Forexample, theaction of theagriculturalfungicidenabam is dueto it beingmetabolisedtotheactivediisothiocyanate. N-Methylation of nabamyields an analoguethat is in activebecause it cannot be metabolisedtotheactivediisothiocyanate.

  27. Methylation can alsoreducetheunwantedsideeffects of a drug. Forexample, mono-and di-ortho-methylationwithrespecttothephenolichydroxygroup of paracetamolproducesanalogueswithreducedhepatotoxicity. It is believedthatthisreduction is duetothemethylgroupspreventingmetabolichydroxylation of theseorthopositions.

  28. Largeralkylgroupswillhavesimilareffects. However, as the size of thegroupincreasesthelipophilicitywillreach a pointwhere it reducesthewatersolubilityto an impracticallevel. Consequently, mostsubstitutionsarerestrictedtomethylandethylgroups.

  29. Halogengroups Theincorporation of halogenatomsinto a leadresults in analoguesthataremorelipophilicandsolesswatersoluble. Consequently, halogenatomsareusedtoimprovethepenetration of lipidmembranes. However, there is an undesirabletendencyforhalogenateddrugstoaccumulate in lipidtissue. Thechemicalreactivity of halogenatomsdepends on boththeirpoint of attachmenttotheleadandthenature of thehalogen. Aromatichalogengroupsare far lessreactivethanaliphatichalogengroups, which can exhibitconsiderablechemicalreactivity. Thestrongestandleastreactive of thealiphaticcarbon–halogenbonds is the C–F bond. It is usuallylesschemicallyreactivethanaliphatic C–H bonds. Theotheraliphatic C–halogenbondsareweakerandsomorereactive, theirreactivityincreasing as onemovesdowntheperiodictable. Theyarenormallymorechemicallyreactivethanaliphatic C–H bonds.

  30. Consequently, themost popular halogensubstitutionsarethelessreactivearomaticfluorineandchlorinegroups. However, the presence of electronwithdrawing ring substituentsmayincreasetheirreactivitytounacceptablelevels. Trifluorocarbongroups (-CF3) aresometimesusedtoreplacechlorine as thesegroupsare of a similar size. Thesesubstitutionsavoidintroducing a veryreactivecentreandhence a possible site forunwantedsidereactionsintotheanalogue. Forexample, theintroduction of themorereactivebromogroup can causethedrugtoact as an alkylatingagent.

  31. Hydroxylgroups Theintroduction of hydroxylgroupsintothestructure of a leadwillnormallyproduceanalogueswithan increasedhydrophilicnatureand a lowerlipidsolubility. Italsoprovides a newcentreforhydrogenbonding, whichcouldinfluencethebinding of theanaloguetoitstarget site. Forexample, theortho-hydroxylatedminaprineanaloguebindsmoreeffectivelyto M1-muscarinic receptorsthanmany of itsnon-hydroxylatedanalogues.

  32. Theintroduction of a hydroxygroupalsointroduces a centrethat, in thecase of phenolicgroups, couldact as a bacterioside, whilstalcoholshavenarcoticproperties. However, the presence of hydroxygroupsopens a newmetabolicpathwaythat can eitheract as a detoxificationrouteorpreventthedrugreachingitstarget.

  33. Basic groups Thebasicgroupsusuallyfound in drugsareamines, includingsome ring nitrogenatoms, amidinesandguanidines. Allthesebasicgroups can form salts in biologicalmedia. Consequently, incorporation of thesebasicgroupsintothestructure of a leadwillproduceanaloguesthathave a lowerlipophilicity but an increasedwatersolubility. Thismeansthatthemorebasic an analogue, themorelikely it will form saltsandthelesslikely it will be transportedthrough a lipidmembrane

  34. Theincorporation of aromaticaminesintothestructure of a lead is usuallyavoided since aromaticaminesareoftenverytoxicandareoftencarcinogenic.

  35. Carboxylicandsulphonicacidgroups Theintroduction of acidgroupsintothestructure of a leadusuallyresults in analogueswith an increasedwater but reducedlipidsolubility. Thisincrease in watersolubilitymay be subsequentlyenhancedby in vivo salt formation. In general theintroduction of carboxylicandsulphonicacidgroupsinto a leadproducesanaloguesthat can be morereadilyeliminated (seeTable 12.2). Theintroduction of carboxylicacidgroupsintosmallleadmoleculesmayproduceanaloguesthathave a verydifferenttype of activityorareinactive. Forexample, theintroduction of a carboxylicacidgroupintophenolresults in theactivity of thecompoundchangingfrombeing a toxicantiseptictothelesstoxic anti-inflammatorysalicylicacid.

  36. Similarly, theincorporation of a carboxylicacidgroupintothesympathomimeticphenylethylaminegivesphenylalanine, which has nosympathomimeticactivity. However, theintroduction of carboxylicacidgroupsappearstohavelesseffect on theactivity of largemolecules. Sulphonicacidgroups do not usuallyhaveanyeffect on thebiologicalactivity but willincreasethe rate of excretion of an analogue.

  37. Thiols, sulphidesandothersulphurgroups Thiolandsulphidegroupsare not usuallyintroducedintoleads in SAR studiesbecausetheyarereadilymetabolisedbyoxidation (seeTable 12.1). However, thiolsaresometimesintroducedinto a leadstructurewhenimproved metal chelation is theobjective of theSAR study. Forexample, theantihypertensivecaptoprilwasdevelopedfromtheweaklyactivecarboxyacylprolinesbyreplacement of their terminal carboxylicacidgroupwith a thiolgroup, which is a far bettergroupforformingcomplexeswithmetalsthancarboxylicacids. Theintroduction of thioureaandthioamidegroups is usuallyavoided since thesegroupsmayproducegoitre, a swelling on theneckduetoenlargement of thethyroidgland.

  38. Changingtheexistingsubstituents of a lead Analogues can also be formedbyreplacing an existingsubstituent in thestructure of a leadby a newsubstituentgroup. Thechoice of groupwilldepend on theobjectives of thedesignteam. It is oftenmadeusingtheconcept of isosteres. Isosteresaregroupsthatexhibitsomesimilarities in theirchemicaland/orphysicalproperties. As a result, they can exhibitsimilarpharmacokineticandpharmacodynamicproperties. Inotherwords, thereplacement of a substituentbyitsisostere is morelikelytoresult in theformation of on analoguewiththesametype of activity as theleadthanthetotallyrandomselection of an alternativesubstituent. However, luckstillplays a partand an isostericanaloguemayhave a totallydifferenttype of activityfromitslead.

  39. ClassicalisostereswereoriginallydefinedbyErlenmeyer as beingatoms, ionsandmoleculeswhich had identicaloutershells of electrons. Thisdefinition has nowbeenbroadenedtoincludegroupsthatproducecompoundsthat can sometimeshavesimilarbiologicalactivities.Thesegroupsarefrequentlyreferredto as bioisosteres in ordertodistinguishthemfromclassicalisosteres.

  40. A largenumber of drugshavebeendiscoveredbyisostericandbioisostericinterchanges. Forexample, thereplacement of the 6-hydroxy group of hypoxanthineby a thiolgroupgavethe anti tumourdrug 6-mercaptopurine whilstthereplacement of hydrogen in the 5-position of uracilbyfluorineresulted in fluorouracil, which is also an anti tumouragent. However, not allisostericchangesyieldcompoundswiththesametype of activity: thereplacement of the -S- of theneurolepticphenothiazinedrugsbyeither -CH––CH- or -CH2CH2- producesthedibenzazepines, whichexhibitantidepressantactivity.

  41. Table-Examples of bioisosteres. Eachhorizontalrowrepresents a group of structuresthatareisosteric.

  42. Figure-Examples of drugsdiscoveredbyisostericreplacement

  43. Drugandanaloguesynthesis Startingmaterials Thechoice of startingmaterials is important in anysyntheticroute. Common sense dictatesthattheyshould be chosen on thebasis of whatwillgivethebestchance of reachingthedesiredproduct. Furthermore, in allcasesthestartingmaterialsshould be cheapandreadilyavailable. Howeverthis is not alwayspossiblewhencarryingouttheinitialsynthesis of a specificanalogue. Thejob of theprocesschemist is toconverttheseexpensiveanaloguesynthesesintomoreviablemanufacturingmethods.

  44. Practicalconsiderations Thechemicalreactionsselectedfortheproposedsyntheticpathwaywillobviouslydepend on thestructure of thetargetcompound. However, a number of general considerationsneedto be borne in mindwhenselectingthesereactions: 1. Theyields of reactionsshould be high. This is particularlyimportantwhenthesyntheticpathwayinvolves a largenumber of steps. 2. Theproductsshould be relativelyeasytoisolate, purifyandidentify. 3. Reactionsshould be stereospecific as it is oftendifficultandexpensivetoseparateenantiomers. However, theexclusiveuse of stereospecificreactions in a syntheticpathway is a conditionthat is oftendifficulttosatisfy. 4. Thereactionsused in theresearchstage of thesynthesisshould be adaptabletolargescaleproductionmethods. Thereactionsusedbyresearchworkersfrequentlyuseexpensiveexoticreagentsand it is thejob of pharmaceuticaldevelopmentchemiststofindsimplercost-effectivealternatives.

  45. Theoveralldesign Allapproachesarebased on a knowledge of thechemistry of functionalgroupsandtheirassociatedcarbonskeletons. Thedesignmayresult in either a linearsynthesis, whereone step in thepathway is immediatelyfollowedbyanother: A -> B -> C-> D-> tothetargetmolecule

  46. or a convergentsynthesis, wheretwoormoresections of themoleculearesynthesisedseparatelybeforebeingcombinedto form thetargetstructure.Inbothcases, thedisconnectionapproachmay be usedtodesignthepathwayandidentifysuitablestartingmaterials. • Alternativedesignstrategiesthat can also be usefullyemployedtodesign a synthesisare: • findingcompoundswithsimilarstructurestothetargetmoleculeandmodifyingtheirsyntheticroutes, ifknown, toproducethetargetcompound • modifyingnaturalproductswhosestructurescontainthe main part of thetargetstructure

  47. Theuse of protectinggroups Thedesign of syntheticpathwaysoftenrequires a reactionto be carriedout at onecentre in a molecule, theprimaryprocess, whilstpreventing a secondcentrefromeitherinterferingwiththeprimaryprocessorundergoing a similarunwantedreaction. Thisobjectivemay be achievedbycarefulchoice of reagentsandreactionconditions. However, an alternative is tocombinethesecondcentrewith a so-calledprotectinggroupto form a structurethatcannotreactundertheprevailingreactionconditions. A protectinggroupmust be easytoattachtotherelevantfunctionalgroup, forma stablestructurethat is not affectedbythereactionconditionsandreagentsbeingusedtocarryouttheprimaryprocessandshould be easilyremovedonce it is nolongerrequired (Table 15.1). However, in somecircumstances, protectinggroupsmay not be removed but convertedintoanotherstructure as part of thesynthesis.

  48. Table-Examples of protectinggroups. Theconditionsusedwillvaryandsoonlytheprincipalreagentsareshown.

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