Antidiabetic.pdf

Antidiabetic Agents for B Pharm Sem V (PCI)

1. Antidiabetic Agents
For B Pharm (Sem V, PCI)

2. CONTENTS:
Insulin and its preparations
Sulfonyl ureas: Tolbutamide*, Chlorpropamide, Glipizide, Glimepiride.
Biguanides: Metformin.
Thiazolidinediones: Pioglitazone, Rosiglitazone.
Meglitinides: Repaglinide, Nateglinide.
Glucosidase inhibitors: Acrabose, Voglibose.

3. Diabetesmellitusisametabolicdisordercharacterizedbyhyperglycemiaandassociatedwithimpaired
fat,carbohydrate,andproteinmetabolism.Thediseaseistheresultofdefectsininsulinsecretion
and/orinsulinaction,whichprogressivelyleadstochronicmicrovascular,macrovascular,and
neuropathiccomplications.
wasformerlycalledinsulin-dependent
diabetesmellitusorjuvenile-onsetdiabetes.It
accountsfor5%to10%ofpatientswith
diabetesandislargelyrecognizedasan
autoimmunediseasewherebytheb-cellsare
destroyedbythebody’sownantibodies.
Becausethepancreascannolongerproduce
insulin,type1diabeticshaveanabsolute
requirementforexogenousinsulin.
Symptoms:polydipsia(thirst),polyuria
(frequenturination),polyphagia(hunger),
weightloss,fatigue,anddiabeticketoacidosis.
diabetes(formerlycallednon–insulindependent
diabetesmellitusoradult-onsetdiabetes)
accountsfor90%to95%ofadultcasesofdiabetes.Type2
diabetesslowlyprogressesfromastatewherethepatient
developsinsulinresistancetoastatewherethepancreasloses
itsabilitytoproduceenoughinsulintocompensateforthe
insulinresistanceofperipheraltissues.
(*Insulinresistanceisthestatewheretissuesdonotutilize
insulinproperly).
Insulinresistanceisassociatedwithanumberofphysiologic
riskfactors(hyperinsulinemia,hypertension,dyslipidemia,
hypercoagulation,proinflammatorystate,andabdominal
obesity)mostcommonlyreferredtoas“themetabolic
syndrome.”
Types ofdiabetes

4. https://www.news-medical.net/health/Diabetes-Mellitus-Subtypes.aspx

5. Insulinplaysavitalroleinanumberofbiochemical
processes,includingmorethan100examplesofgene
regulation.
Intheliverandmuscletissues,insulin
✓promotesthestorageofexcessglucoseasglycogen.
✓suppresseshepaticglucoseproductionandthebreakdown
offatsintofattyacidsandglycerol.
✓facilitatesabsorptionofaminoacidsintocellsandtheir
conversionintoproteins.
✓convertsexcesscarbohydrates,whichcannotbeusedas
glycogen,intofatsandthenpromotesthestorageoffatin
adiposetissue.
Whenboundtocellsurfacereceptors,insulininitiatesacascadeofeventsthatareintegralto
thetransportofglucoseintocells.

6. Theinsulinreceptorisalarge,transmembrane
glycoproteincomposedoftwoαsubunitsand
twoβsubunitslinkedbydisulfidebonds.
Theαsubunits,whichpossesstheinsulin
bindingdomain,arelocatedextracellularly.
Theβsubunitsaretransmembraneproteins
thatalsopossessenzymaticactivity.
Wheninsulinbindstoandactivatesthis
receptor,intramolecularautophosphorylation
ofseveralβ-subunittyrosineresiduesoccurs.
Thisenhancesthereceptor'styrosinekinase
activity,whichisresponsiblefor
phosphorylatinginsulinreceptorsubstrates
(IRS-1toIRS-4).
Thesephosphorylatedproteinsserveasintracellularsignalsforprocessesessentialtocellsurvivaland
proliferation.
Thisincludestranslocationoftheglucosetransporterstothecellsurfaceandsynthesisofglycogen,
protein,mRNAs,andnuclearDNA

7. Theinsulinanalogsavailablefortreatmentofdiabetesareclassifiedaccordingtotheirrateofonset
anddurationofaction.
Structure–activityrelationshipstudiesrevealedthatvariationsorremovalofaminoacidresidues
fromtheC-terminusoftheBchaincouldinfluencetherateofdimerformationwhilenot
drasticallychangingthebiologicactivity.Inhibitingdimerformationcanallowforrapid-acting
insulin.
Thus,thevariousinsulinanalogsthathavebeendevelopedhavesubstitutionsinoradditionstotheC-
terminusoftheBchainstartingatresidueB28.Theresultinganalogshaveeitherafasteronsetora
longerdurationofactionrelativetonativeinsulin.
TheseanalogsareallproducedbyrecombinantDNAtechnologyusingamodifiedDNAtemplate.

8. Lispro
✓Rapid-acting insulin analogs include insulin lisproinwhichthe LysB29 is switched withProB28.
✓These modifications, as already stated, result in insulin analogs that do not form dimers in solution
and that dissociate immediately into monomers, producing a very quick onset ofaction.
✓Pharmacodynamically, lispro, bind as well to insulin receptors as human insulin and havea
✓low mitogenic potency. Mitogenic activity is the ability of insulin to induce cell division and is
believed to be associated with insulin’s binding to insulin-like growth factor receptors I andII.
✓Lispro have an onset of action within 15 minutes, peak activity at 30 to 90 minutes, and duration
of action of 3 to 4hours.

9. Glargine
✓Thefirstlong-actinginsulinanalogtobeintroducedtothemarketwasinsulinglargine.This
analogresultsfromthereplacementofAsnA21byglycine(Gly)andtheadditionoftwoArg
aminoacidstotheC-terminusoftheBchain.
✓Theresultinganaloghasanisoelectricpointcloseto7,butisformulatedatanacidicpH4,where
itiscompletelywatersoluble.Aftersubcutaneousinjectionoftheacidicsolutionintotissueat
physiologicpH(approximately7.4),theincreaseinpHto7.4causestheanalogtoprecipitate
fromsolution,formingmicrocrystalsofinsulinhexamers,whichthenslowlydissociateinto
insulinmonomers.
Theslowdissolutionofthe
hexamertomonomericinsulin
fromthesiteofinjectionresultsin
anonsetof1to4hours,apeak
between5and24hours,anda
durationof20to24hours,which
representsafairlyconstantrelease
ofinsulinglargineover24hours,
givinganalmostpeaklessprofile.

10. Sulfonylureas

11. Mechanism ofAction
✓The mechanism of action of the sulfonylureas is to stimulate the release of insulin from the
functioning β-cells of the intactpancreas.
✓Sulfonylureas acutely lower plasma glucose by
stimulating the release ofinsulin.
✓The primary mechanism is throughbinding to
sulfonylurea receptors (SUR-1)on
functioning pancreatic beta-cells.
✓Binding closes the linked ATP-sensitive
potassium channels,which leads to decreased
potassium influx and subsequent depolarization
of the beta-cell membrane.
✓Voltage-dependent calcium channels openand result
in an influx of calcium, causing translocation
and exocytosis of secretory granules of insulin to
the cell surface.
✓The sulfonylureas may have other actions, such as
inhibition of secretion of glucagon and action at post
receptor intracellular sites to increase insulinactivity.
https://www.clinicalcorrelations.org/2007/10/17/clinical-pharmacy-corner-sulfonylureas/

12. SAR of SUR

13. The sulfonylureas may be represented by the following generalStructure
The aliphatic group, R
conferslipophilic properties
to the molecule.
Maximal activity results
when R consists of three to
six carbonatoms.
Aryl groups at R generally
give toxic compounds.
TheRgrouponthe
aromatic ring primarily
influences the duration of
action of the compound.
Theseareureaderivativeswithanaryl
sulfonylgroupinthe1-positionandan
aliphaticgroupatthe3-position.
Infirst-generationanalogues,thearomaticsubstituentisa
relativelysimpleatomorgroupofatoms(e.g.,methyl,amino,
acetyl,chloro,bromo,methylthio,ortrifluoromethyl);however,
thesecond-generationanalogueshavealargerp-(β-
arylcarboxyamidoethyl)groupthatleadstosignificantlyhigher
potency
Sulfonylureas are weak acids, with pKavalues of approximately 5.0 with proton dissociation from the
sulfonyl-attached nitrogen of the urea.

14. Tolbutamide
1-butyl-3-(p-tolylsulfonyl)urea
Chlorpropamide
1-[(p-chlorophenyl)-sulfonyl]-3-propylurea
Thisdrugismoreresistanttoconversionto
inactivemetabolitesthanistolbutamideand,asa
result,hasamuchlongerdurationofaction.
Onestudyshowedthatabouthalfofthedrugis
excretedasmetabolites,withtheprincipalone
beinghydroxylated(ωandω-1)inthe2-position
ofthepropylsidechain.

15. Glipizide:1-cyclohexyl-3-[[p-(2-(5-methylpyrazinecarboxamido) ethyl]phenyl]sulfonyl]urea is a
cyclohexylsulfonylurea analog similar to acetohexamide and glyburide, with a pKa of5.9.
Metabolismofglipizideisgenerallythrough
oxidationofthecyclohexaneringtothep-hydroxy
andm-hydroxymetabolites.
Aminormetabolitethatoccursinvolvesthe
N-acetylderivative,whichresultsfromthe
acetylationoftheprimaryaminefollowinghydrolysis
oftheamidesystembyamidaseenzymes.
2
nd
GENERATION

16. Metabolism

17. Glimepiride:
1-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-
pyrroline-1-carboxamido)ethyl]phenyl]
sulfonyl]-3-(trans-4-methylcyclohexyl)
urea,isverysimilartoglipizidewiththe
exceptionoftheirheterocyclicrings.
Insteadofthepyrazineringfoundin
glipizide,glimepiridecontainsa
pyrrolidinesystem.
Itismetabolizedprimarilythrough
oxidationofthealkylsidechainofthe
pyrrolidine,withaminormetabolicroute
involvingacetylationoftheamine.

19. Non-Sulfonylureas
(Meglitinides)

20. ➢Meglitinideistheprototypestructurethatdefinesthisclassofinsulinsecretagogues.
Themetaglinidesarenonsulfonylureaoralhypoglycemicagentsusedinthemanagementof
type2diabetes(non–insulin-dependentdiabetesmellitus,NIDDM).Theseagentstendtohave
arapidonsetandashortdurationofaction.
➢Muchlikethesulfonylureas,theseinduceinsulinreleasefromfunctioningpancreatic
cells.Themechanismofactionforthemetaglinides,however,differsfromthatofthe
sulfonylureas.Themechanismofactionisthroughbindingtospecificreceptorsintheβ-
cellmembrane,leadingtotheclosureofATP-dependentKchannels.TheKchannel
blockadedepolarizestheβ-cellmembrane,whichinturnleadstoCa2influx,increased
intracellularCa2,andstimulationofinsulinsecretion.

21. ➢Therearetwomajordifferencesbetweentheseseeminglysimilarclassesofagents.
➢Thefirstisthatthemetaglinidescausemuchfasterinsulinproductionthanthe
sulfonylureas.Asaresult,themetaglinidesshouldbetakenduringmeals,asthe
pancreaswillproduceinsulininamuchshorterperiod.
➢Theseconddifferenceisthattheeffectsofthemetaglinidesdonotlastaslongasthe
effectsofthesulfonylureas.Theeffectsofthisclassappeartolastlessthan1hour,
whereassulfonylureascontinuetostimulateinsulinproductionforseveralhours.
➢One advantage of a short duration of action is that there is less risk ofhypoglycemia.

22. Repaglinide:(+)-2-ethoxy-4-[N-[3-methyl-1(S)-[2-(1
piperidinyl)phenyl]butyl]carbamoyl-methyl]benzoicacid
representsanewclassofnonsulfonylureaoralhypoglycemic
agents.Withafastonsetandashortdurationofaction,the
medicationshouldbetakenwithmeals.
Nateglinide:Althoughnateglinide,N-(4
isopropylcyclohexanecarbonyl)-D-phenylalanine, belongs to
the metaglinides, it is a phenylalanine derivative and represents
a novel drug in the management of type 2diabetes.
It is oxidized by CYP 3A4, and the carboxylic acid may be
conjugated to inactive compounds. Less than 0.2% is
excreted unchanged by the kidney, which may be an
advantage for elderly patients who are renallyimpaired.
Themostcommonsideeffectinvolveshypoglycemia,resultinginshakiness,headache,coldsweats,
anxiety,andchangesinmentalstate.

23. Thiazolindiones(TZD)
INSULIN SENSITIZERS, PEROXISOME PROLIFERATOR
ACTIVATED RECEPTOR [PPAR] AGONISTS,GLITAZONES

24. Thethiazolindionesrepresentanovelnonsulfonylureaclassofhypoglycemicagentsforthe
treatmentofNIDDM.Muchlikethesulfonylureas,theuseoftheseagentsrequiresafunctioning
pancreasthatcansuccessfullysecreteinsulinfromcells.
Althoughinsulinmaybereleasedinnormallevelsfromthecells,peripheralsensitivitytothis
hormonemaybereducedorlacking.Thethiazolidinedionesarehighlyselectiveagonistsforthe
peroxisomeproliferatoractivatedreceptor-(PPAR),whichisresponsibleforimprovingglycemic
control,primarilythroughtheimprovementofinsulinsensitivityinmusclesandadiposetissue.
Inaddition,theyinhibithepaticgluconeogenesis.Theseagentsnormalizeglucosemetabolismand
reducetheamountofinsulinneededtoachieveglycemiccontrol.
Theyareonlyeffectiveinthepresenceofinsulin.

25. ➢Activators of PPAR-γ in the treatment of insulin resistance and type 2 diabetes mellitus are a much
sought after target, because PPARs are central regulators of lipid, carbohydrate, and inflammatory
pathways and help maintainhomeostasis.
➢They belong to the nuclear hormone receptor superfamily of ligand activated transcription
factorsand are closely related to steroid, retinoid, and thyroid hormonereceptors.
➢This receptor family is comprised of three members: PPAR-α, δ andγ.
▪PPAR-δ is ubiquitously present in tissues of adultmammals,
▪PPAR-αsubtype is abundantly present in tissues catalyzing lipid oxidation, which include the
liver, kidney, and heart.
▪PPAR γ is primarily expressed in adipose tissue, where it helps control itsdifferentiation.

26. Thethiazolidinediones(TZDs)areclassicexamplesofPPAR-γagonistsandarecommonlyreferredto
asthe“glitazones.”Theseagentsweredevelopedwhenclofibricacidanalogswerebeingscreenedfor
antihyperglycemicandlipid-loweringactivity.
Although initially the mechanism of action of the TZDs was unclear, it was soon discovered that they
enhanced adipocyte differentiation by activation of the nuclear hormone receptor superfamily, PPAR . A
ligand, which can be endogenous, upon binding to PPAR, induces a conformational change in the receptor,
thus stabilizing the interaction with the retinoid X receptor and, in turn, resulting in the stimulation of
transcription of targetgenes.
TheendogenousligandsforPPAR-γhavenotbeenidentified;however,studiessuggestthat
certainarachidonicacidmetabolitesandlong-chainunsaturatedfattyacidssuchaslinoleicacidarethe
intrinsicagonists.
PPAR-γagonists,suchastheglitazones,actbyincreasingthesensitivityofcellstoinsulin.The
glitazonesalsodecreasebothsystemicfattyacidproductionandfattyaciduptake,whichcontributeto
increasedsensitizationofcellstoinsulin.
Patientswithtype2diabetesareknowntohavehightriglycerideandlowhigh-densitylipoproteinlevels.
Theglitazonesincreasethelipolysisoftriglyceridesinverylow–densitylipoproteinsand,asaresult,
increasehigh-densitylipoproteinlevels.However,duringthelipolysisofverylow–densitylipoproteins,
theproductionoflow-densitylipoproteinscouldbeamajordrawbacktotheuseofthesedrugs.

27. PPAR-γactivationimprovesglucoseuptakebyskeletalmuscleand,atthesametime,reduces
glucoseproductionbyslowingdowngluconeogenesis.Hence,thesedrugsimprovemetabolismof
glucoseinnotonlydiabeticpatients,butalsoinobeseindividualswhohaveimpairedglucose
tolerance.
Thepharmacophoreresponsibleforactivityisthethiazolidinedionemoiety.
Aphenylringattachedtothecentralnucleusviaamethylenegroupisessentialforactivity,and
inmanyinstances,asaturatedlinkerisfoundtobemorepotentthantheunsaturatedcounterpart.
ThefirstgenerationofTZDsincludespioglitazone,rosiglitazone,andciglitazone.
Therationaleusedforthedevelopmentoftheseagentswasthefactthatthestructureoftroglitazone
(thefirstdruginthisclasstobemarketed)includesthestructureofα-tocopherol,anantioxidant,
whichretardstheoxidationoflow-densitylipoproteins.
However,duetoseveredrug-inducedhepatotoxicityandcardiovasculareffects,troglitazoneand
rosiglitazonehavebeenwithdrawn,leavingpioglitazoneastheonlyclinicallyuseddrugintheTZD
family.

28. Recently, dual PPAR-α/γ agonists have become much sought after targets, and many research groups
are actively involved in synthesizing such bioactive compounds as novel antidiabeticagents.
Combined activation of PPAR-α and PPAR-γ is believed to induce complementary and synergistic
action on lipid metabolism, insulin sensitivity, and inflammation control, possibly circumventing or
reducing the side effects ofPPAR-γ.
Rosiglitazone
Themoleculehasasinglechiralcenterandispresentasaracemate.Evenso,the
enantiomersarefunctionallyindistinguishablebecauseofrapidinterconversion.

29. Rosiglitazone: 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]
benzyl] thiazolidine-2,4-dione.
ThemajorroutesofbiotransformationareN-demethylationand
hydroxylationofthepyridineringpaartotheaminonitrogen,
withCYP2C8.

30. Pioglitazone: 5-(4-[2-(5-ethylpyridin-2-
yl)ethoxy]benzyl)thiazolidine-2,4-dione, the
compound is used as the racemicmixture.
Thisisprimarilyaresultoftheinvivo
interconversion of the two enantiomers. Thus,
there are no differences in the pharmacological
activity of the twoenantiomers.

32. Bigunides

33. Biguanides/ Bisguanidines
Historically, goat's rue (Galega officinalis) had been used in
Europe as a traditional remedy for diabetes. It was
discovered that the active principle in this herb, galegine
(isoamyleneguanidine), apparently also was the toxic
principle in the plant, which caused the deaths of grazing
animals.
In 1918, guanidine itself was found to lower blood glucose levels in animals; however, it was too
toxic for therapeuticuse.
In the 1950s, phenformin was found to have antidiabetic properties and was used in the United
States until 1977, when it was removed from the market because of patient deaths associated with
lactic acidosis.
Metformin was introduced in 1995 in the United States after a track record of safe and effective
use for decades overseas, and it is currently in wideuse.

34. MechanismofAction
Metforminandtheotherbiguanidesaredescribedasinsulinsensitizers.Theircompletemechanism
ofactionhasnotbeenfullyelucidated.
Thebiguanidesactintheliverbydecreasingexcessiveglucoseproduction,mostlikelyviareduced
gluconeogenesisresultingfromanincreasedsensitivitytoinsulin.Theyalsoimproveglucose
utilizationbyrestoringtissuesensitivitytoinsulin.Theyappeartohavetheirmainactioninthe
livermitochondriaviaactivationofadenosine5′-monophosphate–activatedproteinkinase(AMPK).
Metformincanlowerfreefattyacidconcentrationsby10to30%.
Thisantilipolyticeffectmayhelptoexplainthereductioningluconeogenesisthroughreduced
levelsofavailablesubstrate.
Whengivenasamonotherapy,metformintreatmentdoesnotleadtohypoglycemia,soitisbetter
describedasanantihyperglycemicagentratherthanahypoglycemicagent.
Thetherapeuticeffectofmetforminrequiresthepresenceofinsulin,andmetformindoesnot
stimulatethereleaseofinsulinorotherfactors,suchasglucagon.Infact,thesecretionof
adiponectin,aninsulin-sensitizinghormone,appearstobesuppressedbymetformin.

35. TherapeuticApplications
❑Metforminiswidelyusedasamonotherapyorincombinationwithasulfonylureaintype2
diabetes.Foroverweightandobesepatients,itistheagentofchoice.Itiseffectiveinpatientsof
normalweightaswell.
❑Otherbenefitsofmetformintherapyarethepotentialforweightreductionanda15to20%
loweringofplasmatriglycerides.
❑Additionalbenefitsofmetformintherapy,particularlyforpatientswithmetabolicsyndrome,are
increasedfibrinolysisanddecreasedplasminogenactivatorinhibitor-1(PAI-1),an
antithrombolyticprotein.
❑Onestudywithoverweightpatientsgivenmetforminversusconventionaltreatmentreporteda
statisticallysignificant,39%reducedriskofmyocardialinfarction.
Contraindications for metformininclude
✓renal insufficiency,
✓liver disease,
✓alcohol abuse,
✓cardiacinsufficiency,
✓metabolic acidosisor
✓any hypoxia-relatedcondition.

36. Metforminisabisguanidine.
Thisclassofagentsiscapableofreducingsugarabsorptionfromthegastrointestinaltract.Also,
theycandecreasegluconeogenesiswhileincreasingglucoseuptakebymusclesandfatcells.These
effects,inturn,leadtolowerbloodglucoselevels.
Unlikethesulfonylureas,thesearenothypoglycemicagentsbutrathercanactas
antihyperglycemics.Thisdifferenceinnomenclatureiscausedbytheinabilityoftheseagentsto
stimulatethereleaseofinsulinfromthepancreas.
Often,metforminiscoadministeredwith
thenonsulfonylureastoimprovetheefficacy
ofthoseagents.

37. α-GLUCOSIDASE
INHIBITORS

38. ➢α-Amylaseandα-glucosidasearekeyenzymesresponsibleforthemetabolismofcarbohydrates.
Thesalivaryandpancreaticα-amylasesareresponsibleforthebreakdownofcomplex
polysaccharidesintooligo-anddisaccharides,preparingthemforintestinalabsorption.α-
Glucosidase,whichconsistsofmaltase,sucrase,isomaltaseandglucoamylase,isamembrane-
boundenzymepresentinthebrushborderofthesmallintestineinrelativelyhighconcentrations
intheproximalpartofthejejunum.
➢Thisenzymecatalyzestheconversionofthedisaccharidesucroseandmaltoseintoglucose.The
resultingmonosaccharidesarethenabsorbedbytheenterocytesofthejejunumandentersystemic
circulation,aswellasvariousbiochemicalpathwaysfortheproductionofenergy.
➢Thus,inhibitingα-glucosidasewilldelaytheprocessofcarbohydrateabsorptioninthegutby
movingtheseundigesteddisaccharidesintothedistalsectionsofthesmallintestineandcolon.The
resultisthepreventionofglucoseproduction,therebyreducingpostprandialhyperglycemia.
➢Theα-glucosidaseinhibitorswerefirstintroducedin1996withthedrugacarbose.Acarboseisan
oligosaccharideobtainedfromActinomycesutahensisandisthedrugofchoiceinthiscategory.Itis
acompetitiveinhibitorwithahighaffinityforsucraseandalesseraffinityforglucoamylaseand
pancreatica-amylaseinhumans.

39. https://pdb101.rcsb.org/global-health/diabetes-mellitus/drugs/alpha-glucosidase-inhibitors/alpha-glucosidase

40. ❖Naturallyoccurringoligosaccharide,
whichisobtainedfromthe
microorganismactinoplanesutahensis
❖Actasacompetitiveinhibitor,whichin
turnreducestheintestinalabsorptionof
starch,dextrin,anddissacharides.

41. Whenusedinmonotherapy,thereisnoriskofhypoglycemiaandweightgain,asseenwiththefirst-
andsecond-generationsulfonylureas.However,gastrointestinalirritation,bloating,andflatulence
causedbyfermentationofundigestedsugarsinthelargebowelbyintestinalmicrofloraaresome
drawbackscommontoalla-glucosidaseinhibitors.Thesesideeffectscanbeminimizedtoacertain
extentbygradualdosetitrationandtherightcombinationtherapywithotherorallyactive
hypoglycemicdrugs.
Thepresenceofpolyhydroxygroupsonthesecompoundsiscriticalforα-glucosidaseinhibition
activity, because most mimic the natural substrates maltose andsucrose.

42. REFERENCEBOOKS:
1.Foye’s Principles of Medicinal Chemistry, Thomas L. Lemke, David A Williams, Lippincott
Williams &Wilkins.
2.Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, John M.
Beale, John H. Block, Lippincott Williams &Wilkins.