pharmaceutical chemistry - didatticaweb
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PharmaceuticalChemistry
Prof.DanielO.Cicero
Introduction
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OutlineoftheCourse- Introduction,OptimizingDrugBindingAffinity,Drug-like
Properties,Lead-to-DrugDesign(DanielCicero)- Therapeutictargetidentificationfromhitcompounds(AlbertoBresciani)- MedicinalChemistryandthediscoveryofleadcompounds
(VincenzoSumma,StevenHarper)- Drugmetabolismandpharmacokinetics(EdithMonteagudo)- Advancedanalyticaltools(FabioBonelli)- Therapeuticpeptides:developmentandexamplesofnew
drugs(ElisabettaBianchi)
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TheDrugDiscoveryProcess
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TheDrugDiscoveryProcess
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Thephasesofdrugdevelopment
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TheDrugDiscoveryProcess
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Thedrugdiscoveryanddevelopmentprocess
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Thedrugdiscoveryanddevelopmentprocess
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Thedrugdiscoveryanddevelopmentprocess
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MedicinalchemistryTheprimaryobjectiveisthedesignanddiscoveryofnewcompoundsthataresuitableforuseasdrugs.Discoveryordesignofadrugrequires:ü Targetdiscoveryü synthesisofthedrugü methodofadministrationü developmentoftestsandprocedurestoestablishhowit
operatesinthebodyü asafetyassessment
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Drugs
• Drug is any substance presented for treating, curing or preventing disease in human beings or in animals. – Activity: is its pharmaceutical effect on the subject – Potency: is the quantitative nature of that effect
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Drugsideeffects• Drugsactbyinterferingwithbiologicalprocesses,sonodrug
iscompletelysafe.
Overdosecancausecomaanddeath
Canalsocausegastricirritationandoccultbleeding
• Sideeffectsarenotalwaysnon-beneficial;thetermalsoincludesbiologicaleffectsthatarebeneficialtothepatient.
Forexample:promethazine(antihistamine)isusedforthetreatmentofhayfeverbutalsoinducesdrowsiness,whichmayaidsleep.
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Drugresistance(tachyphylaxis)
Occurswhenadrugisnolongereffectiveincontrollingamedicalcondition.Reasons:• Inductionofanenzymethatmetabolizesthedrug(barbiturates)
• Downregulationofreceptors• Appearanceofasignificantlyhighproportionofdrug-resistantstrainsofmicroorganisms(antimalarialandantiviraldrugs;antibiotics)
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DiscoveryofPenicillin
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Sincethen….
• Inlatenineteenthcentury:searchforlesstoxicmedicinesthanthosebasedonnaturalsources
• Introductionofsyntheticsubstances:useofknownpharmacologicallyactivecompoundsasleads
• Synthesisoflead-relatedcompounds:analogues
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Thefirstrationaldevelopmentofsyntheticdrugs
• Ehrlich-Hata(1910):bothbeneficialandtoxicpropertiesofadrugusedforitsevaluation.Moreeffectivedrugsaremoreselectiveforthetarget
• Theysearchedforagentstotreatsyphilis,saferthanAtoxyl.600structurallyrelatedcompoundswerecataloguedusingthetherapeuticindex,leadingtothediscoveryofArsphenaminein1909(useduptothemid1940s)
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TheEhrlichindexrevisited• Theindexusedtodaytakesintoaccountthevariabilityof
individuals:
LD50:lethaldoserequiredtokill50%ofthetestanimalsED50:doseproducinganeffectivetherapeuticresponsein50%ofthetestanimals.
• Thelargeradrug’stherapeuticindex,thegreaterisitsmargin
ofsafety.
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Thetherapeuticwindowforadrug
Aproportionofthedrugiseither:• Lostbyexcretion• Convertedtootherproducts(metabolism)• Boundtobiologicalsitesotherthanitstargetsite
Thedoseadministeredishigherthanthatwhichwouldbeneededifalldrugreachedtheappropriatesiteofbiologicalaction
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SARandQSAR• Structure-activityrelationship(SAR)isnowusedtodescribe
Ehrlich’sapproachtodrugdiscovery:synthesizeandtestaseriesofstructurallyrelatedcompounds
• HanschandFujita(1960s)incorporatedquantitativemeasurementsintoSAR:quantitativestructure-activityrelationship(QSAR)
• OneofthemostsuccessfulusesofQSAR:developmentofantiulceragentscimetidineandranitidine.
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TaxonomyofBiologicalMechanisms
Receptors – agonists antagonists partial agonists inverse agonists
Enzymes – inhibitors Ion Channels –openers
blockers
Protein-Protein – inhibitors
In vivo Effectors
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BiologicalMechanisms2014 Top 50 drugs by Worldwide sales
Enzyme Inhibitor 38%
Ion Channel Modulator
8% Biological
10%
Receptor Agonist
12%
Misc 8%
Receptor Antagonist
24%
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BlockbusterDrugs
NF
NH
O
OH
OH
OOH
CholesterolPfizer
$12.0billion
LipitorHMGCoAinhibitor
PlavixAnti-platelet
S
N
Cl COOMe
ThrombosisBMS/Sanofi-Aventis
$5.0billion
NH
O
O O
O
ONH2
Cl
NorvascCalciumchannelblockerHyper-tension
Pfizer$4.8billion
N
N
OS
N
OO
NexiumProtonpumpinhibitor
Anti-ulcerAstraZeneca$4.8billion
Enzyme
Enzyme
Receptor
Ion-channel
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Enzymefunction
Active Site is tailored to bind the transition state for S P Usually, the substrate & inhibitors bind at the active site Allosteric (non-competitive) binding occurs remotely to the active site
E + S ES E + P #
E Free
Ene
rgy
Progress of Reaction
TS
S
P
S
P
TS
Progress of Reaction
Free
Ene
rgy
NH2
NHNH2NH
OOH
NH2
NHNH2O
OOH
O2iNOS
+ NO+
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Enzymeinhibition–Fourmechanisticcategories
1. Competitive inhibition. Inhibitor competes reversibly with substrate for the active site.
2. Uncompetitive inhibition. Inhibitor binds only to the ES complex, leading to EIS intermediates. This is very rare.
3. Non-competitive inhibition. Inhibitor binds non-covalently to sites other than the active site (Allosteric inhibition). Kinetics are complex and partially inhibited enzymes can still turn over substrate.
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Enzymeinhibition–Fourmechanisticcategories
N
S
O
NH
p-OH-Ph
O
CO2H
NH2
NH
SOH
NH
p-OH-PhO
CO2H
O
NH2
N
O
O
OH
CO2H
OH
OH
O O
Scys
turnover
irreversibleinhibition
4. Irreversible inhibition. Inhibitor binds covalently, usually to the active site machinery. Also known as Suicide inhibitors. Examples include MAO inhibitors and β-lactamase inhibitors:
Amoxycillin
Clavulanic acid
β
β
β
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Proteases(proteinases,peptidases)
Endopeptidases cleavage site may be anywhere in the substrate Exopeptidases terminal residue (carboxypeptidase, aminopeptidase)
Hydrolytically cleave peptidic amide bonds
Four Mechanistic Classes
Serine
Cysteine (thiol)
Aspartic
Zinc (metallo)
Nucleophile pH preference Endo/Exo
R-CH2OH
R-CH2SH
~7
~7
endo
endo/exo ~7
3-6
endo
endo
H2O
H2O
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ProteaseSpecificity
S3’ S1’ S2
Specificity-Pocket nomenclature (Schechter & Berger, Biochem Biophys Res Com, 1967, 27, 157-162)
prime side non-prime side
S3 S1 S2’
..
substrate N-terminus
Substrate C-terminus
P3'
NH
NH
NH
NH
NH
NH
O
O
O
O
O
P1P3 P2'
P2 P1'
E-XH
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SerineProteasesThrombin, Tryptase , β-Lactamase, Elastase, Chymotrypsin, HCV-NS3
Catalytic triad boosts serine nucleophilicity
enzyme
substrate
O Ser195
NH
NH
O
P1
P1'
H
P1 is the primary specificity site
Inhibitors create or mimic stable tetrahedral
intermediates
β-lactams
trifluoromethyl ketones
saccharins
NO
O
CF3
ONHCOR
SN
O
O OX
NN
HO
O
Asp102
His57
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Thereceptivesubstances• In1905Langleyproposedthatso-calledreceptivesubstancesinthebodycouldaccepteitherastimulatingcompound(causingabiologicalresponse)oranon-stimulatingcompound(preventingaresponse)
• Thisidealeadtothetheoryofreceptors
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Receptors• Receptors are membrane-bound proteins that bind endogenous ligands (usually extracellular) to induce a physiological effect (usually intracellular)
• A receptor is often the first step in a long intracellular signalling cascade leading to physiological effects
• G-Protein Coupled, Seven-Transmembrane Spanning Receptors comprise the majority of known examples
intracellular
extracellular
7TM GPCR
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BindingtoReceptors
R R*
ground-state receptor
no signal
Excited-state receptor
signal
Agonist a ligand that binds to, and provokes a signal from a receptor via conformational changes in the excited state
Antagonist a ligand that binds to a receptor and induces no signal.
Blocks agonist binding. Little conformational change overall
ligands can be proteins, peptides or small molecules
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Typesofreceptors
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TypesofReceptors
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Typesofreceptors
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IonChannelsAll of life exists within an electric potential window of less than one volt
The membrane potential of most cells is 60-70mV
Ion channels regulate passive ion flow through membranes in an electric or concentration gradient
Channels are ion selective and comprise groups of glycoprotein subunits in homo- or heteropolymer arrays. Almost no channels have an open rest state
Channels are involved in cardiac, neuronal and psychiatric disorders
Which ions? Na+ K+ Ca++ ( Cl- )
hERG (IKr) channel: blockade causes prolongation of cardiac Q-T interval
“Long QT syndrome” can lead to sudden death
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hERGChannel
• Thehumanether-a-go-gorelatedgene(hERG)encodestheinwardrectifyingvoltagegatedpotassiumchannelintheheart(IKr)whichisinvolvedincardiacrepolarization.
• InhibitionofthehERGcurrentcausesQTintervalprolongationresultinginpotentiallyfatalventriculartachyarrhythmiacalledTorsadedePointes.
• Anumberofdrugshavebeenwithdrawnfromlatestageclinicaltrialsduetothesecardiotoxiceffects,thereforeitisimportanttoidentifyinhibitorsearlyindrugdiscovery.
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IonChannels
Channel families are complex, but all channels are either
Voltage-gated
or
Ligand-gated
Ligands can be other ions, small molecules or toxins & venoms such as tetrodotoxin, pumiliotoxin, margatoxin & charybdotoxin
Blockbuster antihypertensive drugs have emerged from calcium-channel antagonist programmes – Nifedipine, Nimodipine, Isradipine, Amlodipine
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Theα-adrenoceptor
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Gprotein
• Guaninenucleotide-bindingproteins
• Actasmolecularswitchesinsidecells,andareinvolvedintransmittingsignalsfromavarietyofstimulioutsideacelltoitsinterior
• TheiractivityisregulatedbyfactorsthatcontroltheirabilitytobindtoandhydrolyzeGTPtoGDP.
• WhentheyareboundtoGTP,theyare‘on’,andwhentheyareboundtoGDPtheyare‘off’
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Mechanismofadrenergicreceptorα1couplestoGq,whichresultsinincreasedintracellularCa2+α2couplestoGi,whichcausesadecreaseinneurotransmitterrelease,aswellasadecreaseofcAMPactivityβreceptorscoupletoGs,andincreasesintracellularcAMPactivity
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Drugsactingonareceptor• adrugismosteffectivewhenitsstructureorasignificantpartofits
structure,bothasregardsmolecularshapeandelectrondistribution(stereoelectronicstructure),iscomplementarywiththestereoelectronicstructureofthereceptorresponsibleforthedesiredbiologicalaction
Sincemostdrugsareabletoassumeanumberofdifferentconformations,theconformationadoptedwhenthedrugbindstothereceptorisknownasitsactiveconformation
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Pharmacophore
• Thesectionofthestructureofaligandthatbindstoareceptorisknownasitspharmacophore.
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Newtoolsfordrugdiscovery
Molecularmodelling– allowstheresearchertopredictthe3Dshapesofmoleculesandtarget
– Enablestocheckwhethertheshapeofapotentialleadiscomplementarytotheshapeofitstarget
– Allowstocalculatethebindingenergyliberatedwhenamoleculebindstoitstarget
– Reducedtheneedtosynthesizeeveryanalogueofaleadcompound
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