Introduction to medicinal chemistry For B. Pharm Students

For B. Pharm Students

1. Medicinal Chemistry
Chapter 1 Introduction
College of Pharmacy, SDU

2. Definition
•Medicinalchemistryisachemistry-based
discipline,involvingaspectsofbiological,medical
andpharmaceuticalsciences.Itisconcernedwith
theinvention,discovery,design,identificationand
preparationofbiologicallyactivecompounds,the
studyoftheirmetabolism,theinterpretationof
theirmodeofactionatthemolecularleveland
the constructionofstructure-activity
relationships(SARs).

3. •Inparticular,Medicinalchemistryalso
involvesthediscoveryofnewchemical
entitiesforthetreatmentofdiseasesandthe
systematicstudyofthestructure-activity
relationshipsoftheactivecompounds.Such
studiesprovidethebasisfordevelopmentof
bettermedicinalagentsfromleadcompounds
foundviarandomscreening,systematic
screeningandrationaldesign.

4. •Drugisanysubstancepresentedfortreating,
curingorpreventingdiseaseinhumanbeings
orinanimals.Itmayalsobeusedformakinga
medicaldiagnosisorforrestoring,correcting,
ormodifyingphysiologicalfunctions.

5. •Structure-activityrelationship(SAR)isthe
relationshipbetweenchemicalstructureand
pharmacologicalactivityforaseriesof
compounds.
•Leadcompoundisacompoundthathasa
desirablebiologicalactivitywiththerapeutic
relevance,buttypicallyhassomeshortcoming
thatislikelytobeovercomethroughthe
developmentofanalogs.

6. Emphasis
•1.Chemciallystructuralfeature,physico-chemical
property,stability.
•2.Biological effect,adverse effects,
biotransformationetc.
•3.Structure-activityrelationship,drugtargetsin
livingbodiesaswellasmodeofaction.

7. The important role of
drugs in human society
•Drugshaveirrevocablychangedthefabricof
societybyimprovingboththeindividual
qualityoflifeandlifeexpectancy.
•Someexamplesareshownasfollows:

8. •1.Bacterialandvirusinfections:polio,
smallpox,tuberculosisandrelateddiseases
have,toaverymajorextent,becomeminor
publichealthconcerns.
•2.Anincreaseinlifeexpectancyresulting
fromdrugtherapyhasalsoledtoashiftin
populationdemographicstowardamore
healthy,elderlypopulation.
•3.Drugregimensforbirthcontrolhave
improvedindividuallifechoicesandthe
qualityoflife.

9. •4.HIVproteaseandreversetranscriptase
inhibitorsforthetreatmentofHIVinfectionshave
changedadiseasewithafatalprognosistoa
potentiallychronicone.
•5.Cancerisalsobeingviewedasapotentially
chronic,ratherthanfataldiseasewithnewer,non-
cytotoxicapproaches.
•Notes:HIV,Humanimmunodeficiencyvirus

10. Section 1
Origins of Medicinal Chemistry
1.Earlyinvestigationsofnaturalproducts
•1.1.Intheso-calledpre-scientificera
•Naturalproductshavingahistoryasfolk
remedieswereinuse.Foreexamples,opium,
belladonna,cinchonabark,etc.Manydrugs
originallyusedasfolkremedies,nowadays,
havebeenabandoned.

11. •1.2.Inthelateeighteenthandearlynineteenth
centuries,chemicalexperimentationled
ultimatelytoitsuseinthediscoveryofnew
drugs.
•In1853,HenryHowconceivedtheideathat
functionalgroupsinnaturalproductsmightbe
modifiedbychemicalreagents.
Heheatedmorphinewithmethyliodide,hopingto
convertthealkaloidtocodeine.Heobtained,however,a
newsubstanceofthequaternarysaltofmorphine.HO
O
H OH
N

12. •In1898,thefirstcommerciallyavailable
semisyntheticmorphinederivative(ethylether)
wasintroducedasacoughsedativeinpreference
tocodeineorotheropiates.
•Meanwhile,diacetylmorphinewasintroducedasa
saferpainrelieverthanmorphine.Itquickly
becamepopularthroughouttheworld.
•Fouryearspassedbeforeitsaddictivepropertiesofheroin
wererecognized.Lawswerelaterpassedbygovernments
torestrictitsuse.

13. •1.3.DevelopmentsofMCLeadingtoVarious
MedicinalClassesofDrugs
•Duringthe1840s,thefirstuseofsynthetic
organicchemicalswereintroducedfor
anesthesiaduringatoothremoval,suchas
nitrousoxide,ether,andchloroform.
•In1864,barbituricacidhadbeensynthesizedas
ausefulhypnotic.

14. •In1875,salicylicacidwasintroducedasa
possiblecurefortyphoidfever.Itwasfoundto
beaneffectiveantipyretic.
•In1899,Aspirinwasmarketedasanantipyretic
withouttheunpleasantsideeffects.This
indicatedthatthechemicalstructuresfrom
naturalproductswerechangedintobetterdrugs.
•MedicinalChemistrybegan.

15. 2.FastDevelopment from 1900’s to 1960’s
•1920’s~1930’s:Anesthetics,Hypnotics,Analgesics
wereusedextensively.Inresearchforfunctional
“pharmacophore”,structure-functionrelationship
wasinvestigatedgradually.

16. •After1930’s:Thedevelopmentofnewdrugswas
speededgreatlybytheclosecombinationof
MedicinalChemistry and Experimental
Pharmacology.
•Theoryofantimetabolitewasformedbyusing
metabolicproductsasleadcompounds.
•Discoveryofpenicillinwhichisthefirstantibiotics
isanepoch-makingachievement.
•Afterward,tetracycline,streptomycin,chloramphenicol,
erythromycinwereintroducedoneafteranother.

17. •In1940’s,thefirstdrugusedfortreatingcancer
asabiologicalalkylatingagentwasnitrogen
mustard,whichbegantumorchemicaltherapy.
•In1960’s,oralsteroidalcontraceptiveagents
werediscovered.Corticosteroidshavebecome
animportantdrugs.

18. •After1950’s,agingdisease,cerebrovascularand
cardiovasculardiseasesbecamefirstreasonfor
humandeath.Newdrugsdesignbasedon
enzymesorreceptorsasdrugtargets.
•In1964,firstβ-Adrenergicblockingagent,
Propranolol,wasmarketed.
•In1979,Nifedipine,CalciumChannelBlockerwas
marketed.
•In1981,Captopril,AngiotensinConvertingEnzyme
(ACE)Inhibitorwaslaunched.

19. Future of Medicinal Chemistry
•New drugswillbe
discoveredorinventedby
investigating human
genomicsandhuman
diseasegenomics.

20. 3. Drug Target and Drug Design
•Mechanismbaseddrugdesign
•Structurebaseddrugdesign
•Knowntargets:480，receptors:45%;enzymes:28%
(Seep5~6)

21. 3.1. ReceptorUsed as Drug Target
•Receptors:Macetylcholinereceptor;adrenergic
receptor;angiotensinreceptor;dopaminereceptor;
serotoninreceptor;opioidreceptoretc.
•Drugseffectingonreceptors：
•Agonist；Antagonist
Drug
Receptor

22. •Agonistisanendogenoussubstanceoradrug
thatcaninteractwithareceptorandinitiatea
physiologicalorapharmacologicalresponse
(contraction,relaxation,secretion,enzyme
activation,etc.).
•Antagonistisadrugoracompoundthat
opposesthereceptor-associatedresponses
normallyinducedbyanotherbioactiveagent.
•Partialagonistisanagonistwhichisunableto
inducemaximalactivationofareceptor
population,regardlessoftheamountofdrug
applied.

23. 3.2. Enzyme Used as Drug Target
•Enzyme:AngiotensinConvertingEnzyme
(ACE),Cycloxygenase（COX
2），β-
Lactamase,AcetylcholineEsteraseetc.
•Drugs effecting on enzyme: Enzyme Inhibitor

24. 3.3. Ion Channal Used as Drug Target
•IonChannal:CalciumIonChannal,Potassium
IonChannal,SodiumIonChannal,ChlorideIon
Channal,etc.
•DrugseffectingonIonChannal:CalciumChannal
Blocker,PotassiumChannalBlocker,Sodium
ChannalBlocker,etc.

25. 3.4. Nucleic Acid Used as Drug Target
•NucleicAcid:RNA,DNA
•Drugs: antiviral agent,
quinolone agent, etc.

26. •Antisensetechnology
•AntisensedrugsareshortstretchesofDAN
analogswhichbindtospecificcomplementary
areasofthemRNA.Indoingso,theycaninduce
anucleasewhichcleavesthemRNAatthesite
ofthebindingorcanphysicallyblocktranslation
orotherstepsinmRNAprocessingand
transport,thusstoppingproteinsynthesis.

27. Flowchart for
evaluation
of new chemical
entities

28. R & D Model of Modern Drugs

29. Section 2
Nomenclature of Drug Substances
•INN:InternationalNon-proprietaryNamesfor
PharmaceuticalSubstance,thatis,common
names bynationalorinternational
nomenclaturecommissions
•ChemicalNamebyinternationalunionfor
pureandappliedchemistry(IUPAC)and
internationalunionofbiochemistry(IUB)

30. •CADN:ChineseApprovedDrugNames
•EnglishChemical Name basedon
nomenclatureofchemicalabstracts(CA)
•Trade Name

31. Questions
•1.Tomasterthefollowingdefinitions:medicinal
chemistry,drug,structure-activityrelationship,
leadcompound,Antisensedrugs.
•2.tobefamiliarwithmainresearchcontentsof
medicinalchemistry.
•3.Tounderstandorginsofmedicinalchemistry.