1
Role of Stereochemistry inDrug Development
Kevin Cusack3/22/2006University of Pittsburgh Lecture
Special thanks to Donald Konopacki
Presentation TitleDate
Company Confidential© 200X Abbott
Drug Development of Stereoisomers
Of 1675 Drugs inPharmacopoeia(2001), most arenatural products
2001 Pharmacopoeia Drugs
475
1200
Natural Product or Natural Product Derived Synthetic Derived
2001 Chirality
469 480461
58
0
100
200
300
400
500
600
Natural Product or Derivative Synthetic
Chiral Single Enatiomers
Of 480 Synthetics inPharmacopoeia (2001),most are not singleenantiomers• Sales exceed $100B
Chem 2320
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Presentation TitleDate
Company Confidential© 200X Abbott
Abbott Natural Product Based - Clarithromycin
OO
O
O
OO
O
O
O
N
O
O
O
O
Chiral
Antibiotic (antibacterial)
Polypeptide synthesis inhibitor
Derivative of erythromicin (streptomyces erythreus)See Woodward synthesis, JACS, 1981, 103, 3210, 3213, 3215
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Abbott Amino Acid Based Drugs
NN
O
N
O O
N
O
O
Chiral
LOPINAVIR
N
O
O
N
N
O
O
N
O
S
N
N
S
Chiral
RITONAVIR
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Presentation TitleDate
Company Confidential© 200X Abbott
Should we be concerned with stereochemistry?
CH3
O
CH3
CH2
dl-Carvone
Gingergrass oil
CH3
O
CH3
CH2
l-Carvone
Spearmint
CH3
O
CH3
CH2
d-Carvone
Caraway seed (rye)
Dill seed oil
Enantiomers often show distinct receptor binding profiles
Olfactory receptor:
Presentation TitleDate
Company Confidential© 200X Abbott
Synthesis of Carvone via Pinene
CH3
O
CH3
CH2
CH3
CH3
CH3
CH3
CH3
CH2
Cl
CH3
CH3
CH2
OH
!-Pinene
DMSO (2 eq)POCl3 (1 eq)
DCM20 min, RT
1. AgOAcHOAc (glacial)1 hour, reflux
2. K2CO3 (aq)
CH3OH, reflux
DMSONEt3
HOP(O)Cl2
LIU H J, NYANGULU J M, TETRAHEDRON LETT 30(38),5097-5098(1989) Based on notes in related1950 paper JACS (1950), 72, 2381.
CH3
Cl
O
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH2
Cl
CH3
CH3
CH3
- HOC(CH3)3
!-Pinene
Only occurs with undistilled t-butyl hypochlorite
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Oxidative Routes via Carveol
MULDOON J, BROWN S N, ORG LETT 4(6),1043-1045(2002).OOI T, OTSUKA H, MIURA T, ICHIKAWA H, MARUOKA K, ORG LETT 4(16),2669-2672(2002).
HIRANO M, KOBAYASHI T, MORIMOTO T, SYNTHETIC COMMUN 24(13),1823-1831(1994).
CH3
O
CH3
CH2
CH3
CH3
CH2
OH
N
O
Al CH3
SO O
C6F
17
1 mol% CatalystToluene21°C, 0.5 h
t-BuCHO (1.2 eq)21°C, 1 h
Carveol Carveone
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Other Advantages of Single Enantiomers inPharmaceuticals
• Reduction of total dose• Simpler dose-response relationships• Reduction in inter-patient PK/ADME• Reduction in toxicity from inactive stereoisomer
However, this view is too simplistic as it assumes that alldesirable or undesirable properties reside in one enantiomer.
Enantiomers can show distinct receptor binding profiles
Caveat: In vitro binding studies may not predict in vivo clinical outcome
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Opposing Effects of Enantiomers
OH
NH
OH
OH
Albuterol: Bronchodilator for treatment of asthma
• R-isomer has 100x affinity for β2−adrenoceptors• S-isomer activates muscarinic receptors- opposes beneficial effects of R-isomer • Potentcy of R-isomer is greater than expected by extrapolation of racemate
A short synthesis of albuterol. Synthesis (1988), (12), 966-8
OH
NH
CH3
CH3
CH3
OH
OH
O
NH
CH3
CH3
CH3
OH
O
O
OH
O
Cl
OH
O
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Resolution of Benzoate with Chiral Acid
Enantioselective preparation of optically pure albuterol. U.S. (1996), U.S. 5,399,765
OHNH
OH
O
H
O
CH3
CH3
CH3
CH3
O
N
CH3
CH3
CH3
OH
OO
CH3
O
OH
O
OH
O
CH3
OH
O
CH3
OH
OO
CH3
OHNH
OH
H
OH
CH3
CH3
CH3
HBr, DMSOH2O
HNt-Bu1. NaBH4
2. (-)- ditoluoyl-L-tartaricacid3. Na2CO3
BH3SMe2
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Iminoketone Synthesis
Gao, Yun; Hong, Yaping; Zepp, Charles M. Asymmetric synthesis of (R)- and (S)-arylethanolamines from imino ketones. U.S. (1995), US 5442118 A
OHNH
OH
OH
H
CH3
CH3
CH3
O
N
CH3
CH3
CH3
OH
OO
CH3
O
OH
O
OH
O
CH3
OH
O
CH3
OH
OO
CH3
HBr, DMSOH2O
HNt-Bu
Borane redcution3 eq BH3 SMe2,
catalyst (10 mol%)
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Proposed Mechanism
Corey, Helal; Angew. Chem. Int. Ed. Eng., 37, (1998), 1986
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Is racemate ever preferred?
OH
O
OH
O
(S)-(+)-Ibuprofen (R)-(-)-Ibuprofen
Active Inactive
Ibuprofen: Anti-inflammatory
• S-enantiomer responsible for activity• Inhibits PG synthetase
• R-enantiomer undergoes metabolic chiral inversion• Racemate is more effective than predicted by in vitro binding studies
A case where a single enantiomer offers no clinicaladvantage, only the racemate was in clinical use…but
there is a wealth of literature on single isomerpreparation…
Agents and Actions, 1989, 27, 3/4, 455-457
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Synthesis of Ibuprofen via Enzymatic Hydrolysis
Microbiological Transformations 43. Epoxide Hydrolases as Tools for the Synthesis of Enantiopure α -Methylstyrene Oxides: A New and Efficient Synthesis of (S)- Ibuprofen
Journal of Organic Chemistry (1999), 64(14), 5029-5035
O
CH3
CH3
CH3
CH3
CH3
OHCH
3 OH
O
CH3
CH3
CH3
CH3
CH3
HCH
3 OH
CH3
CH3
HCH
3 OH
O
A. niger
enz. extract
(+/-) (R) (S)
+
H2 Pd/C
KMnO4/H2SO4
(S)(S) - Ibuprofen
1. HBR, HOAc2. KOH, MeOH
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Company Confidential© 200X Abbott
Ibuprofen via N-acylboranesultam
CH3
CH3
O
CH3
CH3
CH3
O
O
CH3
CH3
CH3
NR1R
2
O
CH3
CH3
CH3
O
NR1R
2
CH3
CH3
S
OO
NH
CH3
CH3
CH3
O
OH
I2, AgNO3
MeOH, TMOF
Me3Al, DCM
reflux
1. n-BuLi, THF2. MeI, DMPU
95% de
LiOH, H2O2,
THF, H2O
Oppolzer, Wolfgang; Rosset, Stephane; De Brabander, Jef. Asymmetric synthesis of ibuprofen viadiastereoselective alkylation of a homochiral N-acylbornanesultam.
Tetrahedron Letters (1997), 38(9), 1539-1540
Commerciallyavailable
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Ibuprofen via 1,4 Addition to Nitroalkene
Cu-catalyzed asymmetric 1,4-addition of Me3Al to nitroalkenes. Synthesis of (+)- ibuprofen.Tetrahedron Letters (2005), 46(9), 1529-1532
CH3
CH3
O
H
CH3
CH3
NO2
CH3
CH3
NO2
CH3
CH3
CH3
CH3
O
OH
MeNO2, NH4OAc,
ACOH
Henry
2.5 eq Me3Al
2 mol% Cu Thiophene carboxylate4 mol% LigandEt2O, -30°C
NaNO2, AcOH
DMSO, 35°C
81% ee82% ee
Commerciallyavailable
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Company Confidential© 200X Abbott
Ibuprofen via Stereospecific Rearrangement
Stereospecific rearrangements of optically active 2-aryl-3-ethenyloxiranes to give optically active β -ethenylbenzeneethanols: benzyl vs. allyl cations and an efficient synthesis of (S)- ibuprofen.
Tetrahedron Letters (1997), 38(15), 2605-2608
CH3
CH3
O
H
CH3
CH3
OH
CH3
CH3
CH2
O
CH3
CH3
OHH
CH2
CH3
CH3
CH3
O
OH
1. tBuOOHL-(+)-DIPT, Ti(OiPr)4 64%, 84% ee
2. Swern3. Wittig
Et3SiH; BF3 Et2O
67%, 84% ee
95% de
1. TsCl, pyr2. LiEt3BH
1. Ph3P=CHCO2Me
2. DIBAL
3. NaIO4/RuCl3
CH3CN, CCl4, H2O
Commerciallyavailable
Presentation TitleDate
Company Confidential© 200X Abbott
Omeprazole – Example of Non-Carbon Chirality
NH
N
OCH3
S
O
N
CH3
CH3
O
CH3
Omeprazole
Histamine Blocker:
A process for the preparation of substituted (pyridinylmethylsulfinyl)benzimidazole enantiomers.Parthasaradhi Reddy, Bandi; Rathnakar Reddy, Kura; Raji Reddy, Rapolu; Muralidhara Reddy, Dasari.
WO 2003-IN384 20031205
NH
N
OCH
3
S N
CH3
CH3
O
CH3
NH
N
OCH
3
S
O
N
CH3
CH3
O
CH3
(-)-DeiethyltartrateTi-(OiPr)4,
DIPEA, cumenehydroperoxide
Chem 2320
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Company Confidential© 200X Abbott
Enzymatic Routes to Omeprazole
NH
N
OCH3
S
O
N
CH3
CH3
O
CH3
..
NH
N
OCH3
S
O
N
CH3
CH3
O
CH3
..
NH
N
OCH3
S
O
N
CH3
CH3
O
CH3
O
NH
N
OCH3
S N
CH3
CH3
O
CH3
Biotransformation
Enantioselective preparation of pharmaceutically active sulfoxides by bioreductionWO 95-SE1416 19951127
Enantioselective preparation of pharmaceutically active sulfoxides by biooxidation.WO 95-SE1415 19951127
Microbial synthesis of a proton pump inhibitor by enantioselective oxidation of asulfide into its corresponding sulfoxide by Cunninghamella echinulata MK40
Biotechnology Letters (2001), 23(15), 1217-1222
or
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PharmacokineticsStereospecificity can alter adsorption, elimination and cellular transport of drugs
• Different protein binding profiles• Stereoselective cellular transport
Accumulation of drug at specific site
• Genetic differences in expression of metabolic enzymes Example: CYP2D6 expressed as 2 phenotypes- extensive and poor metabolizers
Factors which can effect PK/ADME:
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Company Confidential© 200X Abbott
Ocular hypotensive for reducing intraocular pressure in treatment of glaucoma
OH
OH
CO2H
NH2
L-!-methyldopa
• Stereoselective cellular transport •Initial entry rate of L-isomer is 4.5 x D-isomer• Cmax of L-isomer >2x D-isomer• AUC: L-isomer > D-isomer
• Stereoselective accumulation of L vs. D isomer in rabbit aqueous humour (compartment responsible for therapeutic action)
• D-isomer has even distribution in tissue fluids •Only S-isomer (L) is metabolized and may explain pharmacological profile
• Metabolized to α-methyldopamine and/or α-methylnorepinepherine (Alices story)
α-Methyldopa
Presentation TitleDate
Company Confidential© 200X Abbott
Stereospecific Biotransformation: Metabolism ofAnticancer pro-drug Ifosamide
Both enantiomers aremetabolized by CYP’s
N
P
O O
NH
Cl
Cl
N
P
O O
NH
Cl
Cl
OH
N
P
O O
NH
Cl
Cl
OH
N
P
O O
NH
Cl
Cl
OH
N
P
O O
NH
Cl
Cl
O
N
P
O O
NH2
Cl
NH
P
O O
NH
Cl
H
O
Cl
NH
P
O O
NH
Cl
Cl
O
NH
P
O O
NH
Cl
ClOH
O
NH
P
OH O
NH
Cl
Cl
CYP
CYP
Ring oxidation (Activation)
Sidechain oxidation (Deactivation)
+
+
Ifosfamide
4-hydroxy-ifosfamide
Ketoifosfamide
Aldoifosfamide
AldehydeDehydrogenase
Carboxyifosfamide
Isophosphoramide mustard
Acrolein
Chloracetaldehyde(CNS Toxicity)
N-dechloroethylation (Deactivation)
(R)
(S)
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Clinical Issues
Therapeutic Drug MonitoringDistinct biochemical properties between enantiomers in racematecan compromise accuracy of plasma drug monitoring
N
NH
NH
N
O NH
NH2
NH
O
OH
OOH
O
O
• Leucovorin: Reduced form of folic acid used to rescuepatients treated with folate antagonists• Monitoring of leucovorin levels crucial ensureadequate rescue• S-enantiomer is active and is rapidly taken into cells• R-enantiomer is inactive and does not enter cells• Plasma levels reflect amount of inactive enantiomer• Difficult to correlate plasma levels withpharmacological effect
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ToxicologyMany chiral drugs have undesirable characteristics associated with a specificenantiomer
N
O
O
NH
O
O
Thalidomide
• R-Enantiomer: Sedative• S-Enantiomer: Teratogen
KetamineO
NH
Cl
• S-Enantiomer: Anesthetic• R-Enantiomer: Hallucinogen
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Thalidomide Story
N
O
O
NH
O
O
Thalidomide
• R-Enantiomer: Sedative• S-Enantiomer: Teratogen
• Approved in Germany as a sedative in1957 (UK, Canada, Australia followed)
• Based on animal studies in mice(insensitive to teratogenic effects in utero
• Less potential for death than barbituates
• Later approved as effective anti-emetic inpregnant women
• Reports of deformed babies emerged by1956. Drug withdrawn in 1961.
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Ketamine Synthesis
KetamineO
NH
Cl
• S-Enantiomer: Anesthetic• R-Enantiomer: Hallucinogen
N
OH
CH3
Cl
NH
O
CH3
Cl
PRZEM CHEM 64(10),478-480(1985). IN POLISH
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Scenarios for Development of Enantiopure Chiral Drugs1. De novo development2. “Chiral switch”: Existing racemate to single enantiomer
A patent is attainable if either or both enantiomers are sufficiently pharmacologically different from the racemate. Often the racemate is protected but the enantiomers are not.
Selection Invention: Selects a group of individual novel members from a previously known class based on superior properties
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Rules for Patentability of Selection Invention
1. Must show substantial advantage2. All members must possess it3. Special properties must be defined in clear terms in
specification4. Must be peculiar to the selected group (those skilled in
the art would not expect to find a large number with these properties in
original group
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Example: Fluoxetine . HCl (Prozac- Eli-Lily)
NH
O
CF3
NH
O
CF3
(S)-(+)-Fluoxetine (R)-(-)-Fluoxetine
Biological and pharmacological activity were the same in their trials therefore Lily didn’t consider itadvantageous to seek patents for the individual enantiomers as anti-depressants• Sepracor was granted patents for (S)-(+)-Fluoxetine for migraine headaches and(R)-(-)-Fluoxetine for depression
(S)-(+)-Fluoxetine (R)-(-)-Fluoxetine
• Doesn’t have certain side effects (anxiety, insomnia, nervousness)• Faster onset of action• Increased response rate• Effective for treatment of migraine headaches
• Short half life• Short duration of action• Effective anti-depressant• Effective appetite suppressant
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Synthesis of (S)-(+)-Fluoxetine
NH
O
CF3
(S)-(+)-Fluoxetine
Miles, et al, Tetrahedron, (2001), 57, 9925
H
O OH O
O
CF3
OHO
O
CH2
F
CF3
O
CF3
NH
CH3
Ti(Oi-Pr)4
(S)-BINOL
NaHDME
(si face attack)
RuCl3, NaIO4
(stoichiometric)
Yoshifuji
1. EDC/HOBH2NMe
2. LAH3. 6M HCl, MeOH, 30 min
Chem 2320
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Synthesis of (S)-(+)-Fluoxetine
NH
O
CF3
(S)-(+)-Fluoxetine
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Completion of synthesis
Chem 2320
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Company Confidential© 200X Abbott
Synthesis of (R)-(-)-Fluoxetine
NH
O
CF3
(R)-(-)-Fluoxetine CH2
OH
OH OH
CN
OH
NH2
O
NH2
CF3
O
NH
CF3
CH3
Cl
CF3
(DHQ)2PHAL
K3Fe(CN)6
K2CO3, t-BuOH-H2O
OsO4, 0°C
1. Bu2SnO
p-TsCl, NEt3
DCM2. NaCN, EtOH-H2O
BH3SMe2
NaH,DMSO55°C
1. ClCO2Me
DCM, K2CO3
2. LAH
Kumar, et al, Tetrahedron Asymm., (2004), 15, 3955
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References
Do single enantiomers have something special to offer? Caldwell, John.Division of Biomedical Sciences, Faculty of Medicine, Imperial College School ofMedicine, London, UK. Human Psychopharmacology (2001), 16(Suppl. 2), S67-S71.
Hindmarch, Ian. The enantiomer debate: Current status and future directions.Human Psychopharmacology (2001), 16(Suppl. 2), S101-S104.
Wainer, Irving W.. The therapeutic promise of single enantiomers: Introduction.Human Psychopharmacology (2001), 16(Suppl. 2), S73-S77.
Wainer I W; Granvil C P; Wang T; Batist G Efficacy and toxicity of ifosfamidestereoisomers in an in vivo rat mammary carcinoma model. Cancer research(1994), 54(16), 4393-7.
Wainer I W; Ducharme J; Granvil C P The N-dechloroethylation of ifosfamide:using stereochemistry to obtain an accurate picture of a clinically relevantmetabolic pathway. Cancer chemotherapy and pharmacology (1996), 37(4),332-6.
Agranat, Israel; Caner, Hava. Intellectual property and chirality of drugs. DrugDiscovery Today (1999), 4(7), 313-321.
Sahajwalla, Chandra. Regulatory considerations in drug development ofstereoisomers. Chirality in Drug Design and Development (2004), 419-432.
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