Chemistry 125: Lecture 31
November 17, 2010
Preparing Single Enantiomers
Pharmaceutical Stereochemistry
Nexium, a Chiral Switch
Eribulin synthesis. 3D visualization. The chemical mode of action of omeprazole is
expected to be insensitive to its stereochemistry, making clinical trials of the proposed
virtues of a chiral switch crucial. Manufacturers, physicians, and the public all have
important duties to discharge with respect to drug usage. The FDA supervises clinical trials,
but according to FDA guidelines physicians may use drugs for non-approved purposes.
Preparation of (S)-omeprazole will provides an example of practical preparation of single
enantiomers for various purposes.
For copyright
notice see final
page of this file
Eisai – 7389 (Eribulin)
Purchase 5 stereocenters. In starting materials
Make the rest.
Only One
1 by chiral Simulated Bed Chromatography.
Chiral Separation
2 by allyl silane additions.
2 by asymmetric dihydroxylations.
2 by oxy-michael reactions.
Specific or general selective
3 by asymmetric Ni/Cr reactions.
reactions that preferentially
1 by Jacobsen epoxidation.
form one isomer.
1 by conjugate reduction.
1 by enolate alkylation
1 by ketal formation
19
Stereocenters
Best
regards,
Frank
Who Cares?
Living Things
Food & Drug Administration
Drug Companies
their Lawyers & USPTO (Patent Office)
"Chiral Switch"
Pain Reliever
Ibuprofen (Advil, Motrin)
COOH
Isobutyl
Phenyl
Propionic
Acid
(S) Active Pain Reliever
(R) Inactive
Sold as racemate
Sedative
H
O
N
Thalidomide
O
O
N
O
(S) Sedative
(R) Teratogen
Sold as racemate in Europe
(1957-62)
10,000 birth defects
in vivo racemization (human)
(S)  (R) 0.12 / hr
(R)  (S) 0.17 / hr
?
(S) eliminated 0.24 / hr
(R) eliminated 0.08 / hr
5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2pyridinyl)methyl]sulfinyl}1H-benzimidazole
Gastric Proton Pump Inhibitor (Acid Reflux)
World's largest selling drug in 2000 ($6.2B)
"Omeprazole"
"Prilosec"
4
3
5
2
6
1
3
•• O
4
9
2
5
1
8
omeprazole
Benzimidazole
Pyridine
7
6
OTC?
5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2pyridinyl)methyl]sulfinyl}1H-benzimidazole
Gastric Proton Pump Inhibitor (Acid Reflux)
World's largest selling drug in 2000 ($6.2B)
"Omeprazole"
(racemate)
"Prilosec"
••••••O
"esomeprazole"
"Nexium"
(S)
B I N O C U L A R SS TT EE RR EE O
N
OO
NN
OO
O O
N
Stereoviewing
(S)-Omeprazole - Stereopair View
from X-rayof Ohishi et al. 1989
left eye
fromX-ray of Ohishi et al. 1989
right eye
(S)-Omeprazole - Stereopair View
from X-ray of
Ohishi et al. 1989
How it should
look when you
stare dreamily into
the distance
“through” the
stereo-pair above
until the blue lines
“swim” together
and superimpose.
right-eye view
left-eye view
Central frame
perceived in stereo
Sulfide  Sulfoxide
S••
R'
R
••
R
••
R'
S
O
Gives Racemate of Course
Sulfide  Sulfoxide
H O * O
O
O
O
peroxy acid
Gives Racemate of Course
R'
R
S
+
R'
R
+
O
H
••
••
••
R
S••
n
O
••
R'
d-vacant
+
R'
n
+ S +
R
+
O
H
S
O
H
+
Blocking the Proton Pump
OCH 3
OCH 3
N
N
••
+
+
N
S
S
HN
O
N••
OCH3
N
n
••
OCH 3
HN
+
H+
H3CO
omeprazole
*N
H3CO
O
+
S
O H+
HN
H
H+ makes *
H3CO
C=N
a lower LUMO
N
H
S
HN
O
N
H
H 3CO
H
Blocking the Proton Pump
OCH3
OCH3
+
S
HN
N
H3CO
+
- OH-
N
S
S
N
HN
N
Enzyme
Pump enzyme
is inactivated,
slowing flow of
HCl to stomach.
OCH3
-S ••
n
S * H
O
+
N
- H+
+
HN
O
N
Enzyme
H3CO
H
S
H
H 3CO
At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min.
(“enteric” coating postpones activation during initial passage through acid stomach)
Should “Chiral Switch” to Single
Blocking the Proton Pump
Enantiomer Help Omeprazole?
OCH3
OCH3
active form
+
N
S
HN
N
H3CO
+
- OHS
S
N
HN
N
Enzyme
Pump enzyme
is tied up.
Slows flow of
HCl to stomach.
-S ••
n
OCH3
+
omeprazole
N
+
S * H
O
-H
HN
H
O
N
Enzyme
H3CO
+
S
H
ACHIRAL !
H 3CO
At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min.
(“enteric” coating postpones activation during initial passage through acid stomach)
Should “Chiral Switch” to Single
Enantiomer Help Omeprazole?
No difference between enantiomers after
omeprazole is “activated” by H+ to R-S-O-H
(and rendered achiral).
Still one enantiomer might be more effective in
getting to the key stomach cells that produce acid.
Need single enantiomer for
laboratory and clinical testing.
Proton-Pump Inhibitor Use
by Wellmark Members
(1.75 M participants in IA/SD)
http://www.wellmark.com/health_improvement/reports/ppi/about.htm
>15% of Wellmark members
>6108 worldwide
Chiral
Switch
2003
2000
1988
S
RS
2002
http://www.astrazeneca.com/sites/7/archive/Investors/Presentations/2004/astrazeneca-2004-abr-carolyn-fitzsimons-nexium.pdf
“Nexium Integrates Clinical, Commercial”
Medical Marketing and Media (Dec, 2003)
by Mark Tosh
…Levine, executive director and development brand leader, adds the clinical and
science proficiency as a research
gastroenterologist.
…as Levine and his staff put together
clinical development plans, such as
additional indications or line extensions,
they get commercial input at every stage.
http://findarticles.com/p/articles/mi_qa5351/is_200312/ai_n21340362
purplepill.com
http://www.nexium-us.com/moa/moa.asp (for health professionals)
Nexium Site
PROBLEM: Evaluate whether this series of 7 scenes shows superiority of Nexium.
From FDA Approved Nexium Label
http://www.fda.gov/cder/foi/label/2004/21153slr015_nexium_lbl.pdf
(How !much would you test?)
Four
Clinical
Trials
100
95
Esophagitis % Healed
90
85
8 Weeks
80
(RS)-Omeprazole (20 mg)
(S)-Omeprazole (20 mg)
75
(S)-Omeprazole (40 mg)
4 the dose of S
contained in
20 mg of RS !
70
65
60
4 Weeks
Nexiumproof.com
NEXIUMPROOF.COM
“If…I told you prescription Nexium heals acidreflux…damage better, you’d want proof.”
Nexiumproof.com
NEXIUMPROOF.COM
“And now your doctor has that proof.”
Nexiumproof.com
NEXIUMPROOF.COM
“Recent medical studies prove Nexium heals…
better than the other leading prescription medicine.”
Nexiumproof.com
NEXIUMPROOF.COM
“No wonder they call Nexium
‘the healing purple pill’.”
Nexiumproof.com
NEXIUMPROOF.COM
“So call your doctor today.”
Nexiumproof.com
NEXIUMPROOF.COM
“because, if left untreated,
the damage could get worse.”
Nexiumproof.com
NEXIUMPROOF.COM
Test
H
OCH 3
OCH23CF3
N
N
S
N
O
H
N
H3CO
S
N
O
N
H3CO
Perspectives from a Clinician
Dianne Duffey M.D., FACS
Section of Otolaryngology, Department of Surgery
Yale University School of Medicine
Clinical Trials
• design of a clinical trial
D. Duffey, with permission
– Controlling variables
– Statistically sound
D. Duffey, with permission
• Biostatistics drive clinical trials design
so that if differences are seen, it can be
determined “with reasonable certainty”
that differences observed are not due to
chance
• Are the pharma companies actually
designing their studies so that they can
make legitimate head-to-head
comparisons between competitor
compounds?
D. Duffey, with permission
Duty - Manufacturer
Duty - Physician
• be able to ascertain the validity of
research supporting our choices as
clinicians.
D. Duffey, with permission
• evaluate the literature critically
Duty - Patient
• Be an educated consumer
• Very effective
• www.fda.gov
D. Duffey, with permission
• Direct to patient (DTP) marketing is
ubiquitous
Specialty is Otolaryngology
(ENT)
– Underdiagnosed
– Significant source of morbidity and
decreased quality of life
– Frequently associated with GERD
• GERD: Potential for premalignant disease in
esophagus, significant public health problem
D. Duffey, with permission
• Laryngopharyngeal Reflux (LPR)
Carrau et al; Arch Otolaryngol Head Neck Surg. 2005;131:315-320
D. Duffey, with permission
• It is estimated that 4% to 10% of patients
presenting to an otolaryngology practice
have symptoms and/or findings related to
LPR.
• Laryngopharyngeal reflux is increasingly
recognized as a probable contributing factor
to nonallergic asthma and many ear, nose,
and throat complaints.
• Studies suggest that acid reflux is present in
50% to 80% of patients with asthma,
10% to 20% of patients with chronic cough,
up to 80% of patients with difficult-tomanage hoarseness, and 25% to 50% of
patients with globus sensation.
Reflux
• It’s a big problem
D. Duffey, with permission
• Hence, much money to be made
LP Reflux
• Treatment: PPI, proton pump inhibitors
D. Duffey, with permission
• Reality: PPI are FDA approved
http://www.fda.gov/cder/foi/nda/2003/21-229_Prilosec_approv.pdf
D. Duffey, with permission
Belafsky et al: ENT-Ear, Nose & Throat Journal
Suppl 2,vol 81: September 2002.
D. Duffey, with permission
Belafsky et al: ENT-Ear, Nose & Throat Journal
Suppl 2,vol 81: September 2002.
Drug Development
• 1 in 5 agents in human testing may
be safe and effective enough to gain
FDA approval
www.fda.gov/fdac/special/testtubetopatient/studies.html
D. Duffey, with permission
• Only 5 in 5,000 compounds entering
preclinical testing make it to human
testing
FDA APPROVAL
Prilosec OTC
June 20, 2003
D. Duffey, with permission
http://www.fda.gov/cder/foi/nda/2003/21-229_Prilosec_approv.pdf
• “We completed our review of this
application, as amended. It is
approved, effective on the date of
this letter, for use as recommended
in the agreed-upon labeling text.”
[omeprazole magnesium delayed-release tablets, 20mg]
[for the treatment of frequent heartburn]
D. Duffey, with permission
FDA APPROVAL
Prilosec OTC (2003)
http://www.fda.gov/cder/foi/nda/2003/21-229_Prilosec_approv.pdf
FDA APPROVAL
Nexium
• Esomeprazole magnesium (Nexium)
– Approved for the Risk Reduction of NSAID-associated
Gastric Ulcers
(2004)
– Treatment of pathological hypersecretory conditions including
Zollinger-Ellison Syndrome
(2006)
http://www.fda.gov/cder/foi/nda/2001/21154_Nexium_Approv.pdf
D. Duffey, with permission
– 1) Healing erosive esophagitis;
2) Maintenance of healing of erosive esophagitis; and
3) Treatment of symptomatic gastroesophageal
reflux disease
(2001)
FDA APPROVAL
D. Duffey, with permission
CLINICAL TRIALS
Clinical Trials - drug studies in humans
• Phase I
• Phase II
D. Duffey, with permission
• Phase III
• Phase IV
http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html
Clinical Trials - drug studies in humans
• Phase I
– Healthy volunteers
– Endpoint: side effects
– Determines metabolism and excretion of drug
– N=20-80
D. Duffey, with permission
• Phase II
• Phase III
• Phase IV
http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html
Endpoints
• SAE - Serious adverse event; resulted
in damage to patient, hospitalization,
surgery etc.
• Reported to the FDA during trials
D. Duffey, with permission
• AE - Adverse event, a side effect
•
Phase I
•
Phase II
– Effectiveness
– Preliminary data: effectiveness of drug for a particular disease or
condition
– Comparison to placebo or to a different drug
– Safety and short-term adverse effects studied
– N=dozens - 300
•
Phase III
•
Phase IV
http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html
D. Duffey, with permission
Clinical Trials - drug studies in humans
Clinical Trials - drug studies in humans
• Phase I
• Phase III
– Safety and effectiveness
– Study different populations; different dosages; combination
with other drugs
– N=several hundred - 3,000
• Phase IV
http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html
D. Duffey, with permission
• Phase II
Clinical Trials - drug studies in humans
• Phase I
• Phase II
• Phase IV
– Postmarketing study commitments
– Studies required of or agreed to by a sponsor
– Conducted after FDA approval received
– Gathering additional information about product’s safety,
efficacy or optimal use
http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html
D. Duffey, with permission
• Phase III
Clinical Trials - drug studies in humans
• Phase 0
• Phase I
D. Duffey, with permission
• Phase II
• Phase III
• Phase IV
Clin Cancer Res 2008; 14(12), 2008
Clinical Trials - drug studies in humans
–
–
–
–
–
–
–
–
–
–
Exploratory, first-in-human trials
A.k.a. microdosing studies
Designed to speed up development of promising agents
Establishes very early on whether agent behaves in human
subjects differently that expected from preclinical studies
Single, subtherapeutic dose of drug, small number patients
(n=10-15)
Not targeting efficacy (dose too low for therapeutic effect)
No potential benefit to patient
Endpoint: pharmacodynamic and/or pharmacokinetic
response
Interrogate and refine a target or biomarker assay for drug
effect
Expected effects at nontoxic doses and over short exposure
durations (e.g. <7days)
Clin Cancer Res 2008; 14(12), 2008
D. Duffey, with permission
• Phase 0
Reflux Studies
– No statistically significant difference
between esomeprazole 20mg (n=620) and
omeprazole 20mg (n=626)
– Chose omeprazole 20mg dose because it’s
“the approved dose for this indication”
http://www.fda.gov/cder/foi/label/2007/021153s027s028,021689s008s011lbl.pdf
D. Duffey, with permission
• Sustained resolution (>7days) of
heartburn in patients with erosive
esophagitis
• However, healing of erosive esophagitis was statistically
significantly better for
20mg esomeprazole
(p<0.05) or
40mg esomeprazole
(p<0.001) over
20mg omeprazole
(n = 656, 654, 650)
(n = 588, 588)
• Another study: statistically significantly better for
EO 40mg
(p<0.001) over
O 20mg
(n = 1216, 1209)
• Another study: no difference
EO 40mg
O 20mg
(n = 576, 572)
http://www.fda.gov/cder/foi/label/2007/021153s027s028,021689s008s011lbl.pdf
D. Duffey, with permission
• Another study: no difference
EO 20mg
O 20mg
• How are we able to use these drugs for
LPR?
Carrau et al; Arch Otolaryngol Head Neck Surg. 2005;131:315-320
D. Duffey, with permission
• Approximately 20% to 43% of patients
with LPR experience heartburn, and
18% have esophagitis.
• “Good medical practice and the best interests of the
patient require that physicians use legally available
drugs, biologics and devices according to their best
knowledge and judgement. If physicians use a product
for an indication not in the approved labeling, they have
the responsibility to be well informed about the product,
to base its use on firm scientific rational and on sound
medical evidence, and to maintain records of the
product’s use and effects.
Use of a marketed product in this manner when the
intent is the “practice of medicine” does not require the
submission of an IND [Investigational New Drug] application,
IDE [Investigational Device Exception] or review by an
Institutional Review Board (IRB).
http://www.fda.gov/OC/OHRT/IRBS/offlabel.html
D. Duffey, with permission
“Off-label” Use
of Marketed Drugs
Duty - Physician
• be able to ascertain the validity of
research supporting our choices as
clinicians.
D. Duffey, with permission
• evaluate the literature critically
End of Lecture 31
Nov. 17, 2010
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J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0