patrick6e_casestudy4.ppt

patrick-casestudy

1. © Oxford University Press, 2013
Patrick: An Introduction
toMedicinalChemistry 6e
Case study 4
Oxamniquine

2. © Oxford University Press, 2013HN
CHNH
CH
3
OH
CH
3
O
2N
DEVELOPMENT OFOXAMNIQUINE

3. © Oxford University Press, 2013
1.Schistosomiasis(bilharzia)
Notes
•Secondmostendemicparasiticdiseaseintheworld
•Affects200millionpeopleinthedevelopingworld
•500000deathsperyear
•Water-bornediseasecarriedbyflatworms
•Flatwormspenetrateskinaslarvae
•Femalesproduceeggsthatbecometrappedinorgansand
tissues
•Resultsinsymptomsofthedisease
•Threespecies(mansoni,haematobiumandjaponicum)
•Limitednumberofdrugsavailablein1960s

4. © Oxford University Press, 2013
2.Earlydrugs
Disadvantages
•Stibocaptateisorallyinactive
•Bothdrugsrequirefrequentdosingregimes
•Bothdrugsproducetoxicsideeffects
•NoteffectiveagainstallthreespeciesS
O HN
Me
N Me
Me
Lucanthone Stibocaptate

5. © Oxford University Press, 2013
3.Desiredpropertiesfornoveldrugs
Non toxic
Oral activity
Single dose regime
Activity against all three species

6. © Oxford University Press, 2013
4.Developmentofoxamniquine
Stage1-IdentificationofaleadcompoundLucanthone
S
O HN
Me
N Me
Me

7. © Oxford University Press, 2013
Stage2-Simplification
4.DevelopmentofoxamniquineLucanthone
S
O HN
Me
N Me
Me

8. © Oxford University Press, 2013
•Active in mice
•Inactive in man
•Electronegative Cl present
•Beneficial at position shown
Stage3-Varyaromaticsubstituents
4.Developmentofoxamniquine
Mirasan

9. © Oxford University Press, 2013
4.Developmentofoxamniquine
Stage4-SARstudies
•Sidechainandaromaticringarebothimportantbindinggroups
•Bothnitrogensareimportant
•Nitrogensarepresentonaflexiblechain-conformationalflexibility
•Flexibilitymaybebadforactivity
•Lesschanceofactiveconformationbeingpresentatanyonetime
Mirasan

10. © Oxford University Press, 2013
One bond ‘locked’
Activity increases
Inactive in man, active in monkeys
Rigidification has retained active conformation
Stage5-Rigidification
Two bonds ‘locked’
Activity increases in mice
Rigidification has retained active conformation
NovelstructureandsoworthtestingpreviousstrategiesagainN
Et2NCH2CH2
Cl
Me N
CH2NEt2
Cl
Me
4.Developmentofoxamniquine

11. © Oxford University Press, 2013
Stage6-Varysubstituentsandsubstituentpositionsonaromaticring
•Substitutionpatternonthearomaticringisessential
•Electron-withdrawing groups are best for activity
-replacing Cl with nitro increases activity
•Nitrogroupreducesbasicityofthearomaticnitrogen
•pK
aisincreasedandmoleculeislesseasilyionised
•Passesthroughcellmembranesmoreeasily
4.Developmentofoxamniquine
Weak base Destabilized

12. © Oxford University Press, 2013
Stage7-Varysidechainsubstituents
•Secondaryamineisbetterthanaprimaryortertiaryamineatendofchain
•Optimumlengthofthealkylgrouponnitrogen=4C
•Acylgroupseliminateactivity
•Impliesnitrogenisprotonated
•Impliesnitrogeninteractswithtargetbyanionicinteraction
4.Developmentofoxamniquine
2
o
3
o
1
o
or

13. © Oxford University Press, 2013
TARGET
TARGET
TARGET
No interaction
Sidechaininteractions
4.Developmentofoxamniquine
STERIC
BLOCK
Butyl
residue
Pentyl
residue

14. © Oxford University Press, 2013NH
2CH
2CH
2CH
2CH
3
+
Stage7-Varysidechainsubstituents
•Branchedalkylgroupsincreaseactivity
•Possiblyimpliesstrongervdwinteractionstoabulkypocket
•Benefitinincreasedlipophilicity
- -
4.DevelopmentofoxamniquineNH
2CH
CH3
CH
3
+

15. © Oxford University Press, 2013
•Branchingonsidechaineliminatesactivity
•Preventsmoleculeadoptingactiveconformation
4.Developmentofoxamniquine
Stage7-VarysidechainsubstituentsZero Activity
HN
C
NHRMe
X
Me
H
Zero activity

16. © Oxford University Press, 2013
van der Waals binding region
Ionic binding region
Stage8-Chainextension
•Chainextensioneliminatesactivity
•Impliesweakerinteractions
•Otherstrategiesarenotbeneficial
4.Developmentofoxamniquine
Strong Weak
NH
2RCH
2Het
+
CH
2
CH
2
NH
2
RHet
Chain
extension +

17. © Oxford University Press, 2013
OptimumStructure
Asymmetric centre
4.DevelopmentofoxamniquineHN
CHNH
CH
3
CH
3
CH
3
O
2N

18. © Oxford University Press, 2013
Stage9-DrugMetabolismStudies
•Oxidationofaromaticmethylgroupinvivogivesoxamniquine
•Oxaminiquineistheactivedrug
•Methylanalogueactsasaprodrug
4.DevelopmentofoxamniquineHN
CHNH
CH
3
CH
3
CH
3
O
2N HN
CHNH
CH
3
OH
CH
3
O
2N
Metabolic
oxidation

19. © Oxford University Press, 2013
Stage10-Proposedbindinginteractionstotargetbindingsite
4.Developmentofoxamniquine
Binding site
Binding
regions
Ionic
Van der Waals
Hydrogen bonding
-CH
CH
3
CH3
CH
2
NH
2CH
2
O2N
HN
OH

20. © Oxford University Press, 2013
•Developmenttook11years
•Reachedmarketin1975
•Effectiveasasingledose
•Orallyactive
•TreatsinfectionsofSchistosomamansoni
•Mildsideeffects
•Meets3outoforiginal4aims
•Highlysuccessfulandstillusedinsomecountries(e.g.Brazil)
5.Oxamniquine

21. © Oxford University Press, 2013
Notes
•Inhibitsnucleicacidsynthesisinparasiticcells
•Actsasaprodrug
•Activatedbysulphotransferaseenzymepresentinparasiticcells
6.MechanismofactionOxamniquine
HN
H
N Me
Me
OH
O
2N S ulfate ester
Sulphotransferase
Sulphateester

22. © Oxford University Press, 2013
Notes
6.Mechanismofaction-H
2SO
4 HN
H
N Me
Me
O
2N Alkylating
agent HN
H
N Me
Me
DNA
O
2N
•Sulphategroupactsasagoodleavinggroup
•Degradationtakesplaceaidedbyinfluenceofsecondaryamine
•Producesanalkylatingagent
•ReactswithDNA
DNA

23. © Oxford University Press, 2013
7.SynthesisofOxamniquineN
Me
Me
I N
Cl
Me
II
Cl
2
Na
2CO
3N
H
N Me
Me
Me
III
Me
2CHNH
2HN
H
N Me
Me
Me
IV Ni/H
2
VI Desired isomerV
+
HNO
3
H
2SO
4Oxamniquine
HN
H
N Me
Me
OH
O
2N
2) Microbial
oxidation
1)Separation
of isomers

24. © Oxford University Press, 2013
8.OtherAgents
HycanthoneS
O HN
CH
2OH
N Me
Me
PraziquantelN
N
O
O
•Metaboliteoflucanthone
•Samemechanismofactionas
oxamniquine
•Moreactivethanlucanthone
•Replacedbyoxamniquine
•Recommendedtreatmentfor
schistosomiasisinUK
•Activeagainstallthree
pathogenicstrains
•Expensive
•Noteconomicallyfeasiblein
developingcountries