Structural Modification to Lead Compounds

Structural Modification to LeadCompoundsStructural Modifications• Goals– Increase Potency– Increase Bioavailability– Increase therapeutic index (ratio of drugconcentrations giving undesirable anddesirable effects)e.g., LD 50ED 50(lethal dose for 50% of the test animals)(effective dose to give maximum effect in50% of test animals)• Should therapeutic index be large or small?• Should the threshold value be the same for every disease?Types of Structural Modifications• Homologation• Chain Branching• Ring-chain Transformations• Bioisosterism• PeptidomimeticsHomologationHomologation - increasing size by a constant unit (e.g., CH 2)Effect of carbon chain length on drug potencyFigure 2.3Pharmacokinetic explanation: Increasing chain length increaseslipophilicity and ability to cross membranes; if lipophilicity too high,it remains in the membranePharmacodynamic explanation: Hydrophobic pocket increasesbinding with increasing length; too large and does not fit intohydrophobic pocketTable 2.1Branched chain groupsare less lipophilic thanstraight chain groups.Chain BranchingOften lowers potency and/or changes activity; interferes withreceptor bindingstructure 2.4010-Aminoalkylphenothiazines (X = H)R = CH 2CHNMe 2promethazineCH 3antispasmodic/antihistamine activities predominateR = CH 2CH 2CH 2NMe 2promazinegreatly reduced antispasmodic/antihistamine activitiesgreatly enhanced sedative/tranquilizing activitiesR = CH 2CHCH 2NMe 2trimepazine All bind toCH 3differentreduced tranquilizing activityreceptorsenhanced antipruritic (anti-itch) activity1

Ring-Chain TransformationsTransformation of alkyl substituents into cyclicanalogs, which generally does not affect potency.structure 2.40Trimepazine (2.40, X = H, R =Methdilazine (2.40, X = H, R =similar antipruritic (anti-itch) activities.NNMe 2Me) and) haveChlorpromazine (antipsychotic)(2.40, X = Cl, R = CH 2 CH 2 CH 2 NMe 2 ) and(2.40, X = Cl, R = CH 2 CH 2 CH 2 N )have equivalent tranquilizing effectsRing-chain transformation can have pharmacokineticeffects, such as increased lipophilicity or decreasedmetabolism.BioisosterismBioisosteres - substituents or groups withchemical or physical similarities that producesimilar biological properties. Can attenuatetoxicity, modify activity of lead, and/or alterpharmacokinetics of lead.Classical IsosteresTwo classical isostere definitions:Grimm: groups having same # valence electronsErlenmeyer: groups with identical peripheral electron layersTable 2.2Non-Classical IsosteresTable 2.3Table 2.4Examples of Bioisosteric AnaloguesDo not have the samenumber of atoms and donot fit steric andelectronic rules ofclassical isosteres, buthave similar biologicalactivity.2

Changes in Activity by BioisosterismIf the S in phenothiazine neuroleptic drugs (2.40) isreplaced by -CH=CH- or -CH 2 -CH 2 - bioisosteres,then dibenzazepine antidepressant drugs (2.43)result.Changes resulting from bioisosteric replacements:Size, shape, electronic distribution, lipid solubility, watersolubility, pK a , chemical reactivity, hydrogen bondingEffects of bioisosteric replacement:1. Structural (size, shape, H-bonding are important)2. Receptor interactions (all but lipid/H 2 O solubility areimportant)3. Pharmacokinetics (lipophilicity, hydrophilicity, pK a ,H-bonding are important)4. Metabolism (chemical reactivity is important)Bioisosteric replacements allow you to tinker with whicheverparameters are necessary to increase potency or reduce toxicity.Bioisosterism allows modificationof physicochemical parameters•Multiple alterations may be necessary:•If a bioisosteric modification for receptorbinding decreases lipophilicity, you may haveto modify a different part of the molecule witha lipophilic group.•Where on the molecule do you go to make themodification?PeptidomimeticsPeptides are important endogenous molecules -neurotransmitters, hormones, neuromodulatorsPeptide drugs - analgesics, antihypertensives, antitumor agentsPeptides generally do not make good drug candidates• rapidly proteolyzed in GI tract and serum• poorly bioavailable• rapidly excreted• bind to multiple receptorsPeptidomimetic - a compound that mimics or blocks thebiological effect of a peptide, but without undesirablecharacteristics•Use the peptide as a lead - modify to minimizeundesirable pharmacokinetic properties•Try to mimic structure of the peptide when it isbound to the target receptor•Replace as much of the peptide backbone aspossible with nonpeptide fragments - leave thepharmacophoric groups•Initially, retain conformational flexibility, butthen refine to more conformationally-rigid analogsto hold groups in bioactive conformation.Phenylalanine PeptidomimeticsFigure 2.9Increased lipophilicity and conformationalrigidity - better absorption and poorrecognition by proteases3

Conformationally-Restricted PeptidesSecondary Structure MimeticsFigure 2.11Figure 2.10Scaffold PeptidomimeticsArg-Gly-Asp (RGD)common β-turn motifthat binds to receptorsPeptide Backbone IsosteresPeptide amide bond replaced with alternative groupsTable 2.5structures 2.66-2.69(statine)RGD peptidomimeticsAssigned Reading• 2.2 through the end of 2.2E.4 and 2.2E.7• Problems 2.4 - 2, 5, 6, 7, 12• Part II – copy for in-class peer review 3/22– copy for grading 3/244