Chemistry 125: Lecture 31November 17, 2010

Preparing Single EnantiomersPharmaceutical 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 providess an example of practical preparation of single

enantiomers for various purposes.

For copyright notice see final page of this file

Preliminary

Who Cares?Living Things

Food & Drug Administration

Drug Companiestheir Lawyers & USPTO (Patent Office)

"Chiral Switch"

Eisai – 7389 (Eribulin)Purchase 5 stereocenters.Make the rest.1 by chiral Simulated Bed Chromatography.2 by allyl silane additions.2 by asymmetric dihydroxylations.2 by oxy-michael reactions.3 by asymmetric Ni/Cr reactions.1 by Jacobsen epoxidation.1 by conjugate reduction.1 by enolate alkylation1 by ketal formation

Best regards,

Frank

Only One Chiral Separation

Specific or general selective reactions that preferentially

form one isomer.

In starting materials

19 Stereocenters

Pain Reliever

COOH

Isobutyl

PropionicAcidPhenyl

Ibuprofen (Advil, Motrin)

(S) Active Pain Reliever

(R) Inactive

Sold as racemate

Sedative

Thalidomide

(S) Sedative

(R) Teratogen

Sold as racemate (1957-62)

N

N

OOO

O

H

(S) (R) 0.12 / hr (R) (S) 0.17 / hr

(S) eliminated 0.24 / hr (R) eliminated 0.08 / hr

in vivo racemization (human)

10,000 birth defects

?

O••

5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}1H-benzimidazole

Gastric Proton Pump Inhibitor (Acid Reflux)

World's largest selling drug in 2000 ($6.2B)

"Omeprazole""Prilosec"

omeprazole1

2

34

5

6 12

34

5

67

8

9

BenzimidazolePyridine

OTC ?

O••

5-Methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl}1H-benzimidazole

"Nexium"

O•• ••

Gastric Proton Pump Inhibitor (Acid Reflux)

World's largest selling drug in 2000 ($6.2B)

"Omeprazole""Prilosec"

"esomeprazole"

(racemate)

(S)

N

N

O

O

O

S T E R E OB I N O C U L A R S T E R E O

N

N

O

O

O

Stereoviewing

from X-rayof Ohishi et al. 1989 fromX-ray of Ohishi et al. 1989

(S)-Omeprazole - Stereopair View

left eye right eye

(S)-Omeprazole - Stereopair View

from X-ray ofOhishi et al. 1989

right-eye view left-eye view

Central frame perceived in stereo

How it should look when you

stare dreamily into the distance

“through” the stereo-pair above

until the blue lines “swim” together and superimpose.

Sulfide Sulfoxide

SRR'

••

••

SRR'

O

••

Gives Racemate of Course

+

SRR'

O

••

O

n +++

Sulfide Sulfoxide

SRR'

••

••

OO

OH

peroxy acid

OO••

SRR'

OH

+SR

R'

OH+

••

H+

SRR'

O

••

Gives Racemate of Course

*

nd-vacant

N

SOHN

N

OCH3

H3CO

• •

••

Blocking the Proton Pump

H+

N

SOHN

N

OCH3

H3CO

H

• •

+

H+

N

SOHN

N

OCH3

H3CO

H

+N

SOHN

N

OCH3

H3CO

H

H

+

+n

*

H+ makes *C=N a lower LUMO

omeprazole

n

Blocking the Proton Pump

N

SO

HN

N

OCH3

H3CO

H- H+

+N

SOHN

N

OCH3

H3CO

H

H

+

+S••

Enzyme

-

At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min.

*

(“enteric” coating postpones activation during initial passage through acid stomach)

Pump enzymeis inactivated,

slowing flow of HCl to stomach.

N

SS

HN

N

OCH3

H3CO

Enzyme

- OH-+

S

Blocking the Proton Pump

N

SO

HN

N

OCH3

H3CO

H

+

At 1 < pH < 3 Omeprazole rearranges with t1/2 ~2 min.

ACHIRAL !

(“enteric” coating postpones activation during initial passage through acid stomach)

Should “Chiral Switch” to Single Enantiomer Help Omeprazole?

- H+

n*

S••

Enzyme

-

N

SOHN

N

OCH3

H3CO

H

H

+

+N

SS

HN

N

OCH3

H3CO

Enzyme

- OH-+

Pump enzymeis tied up.

Slows flow of HCl to stomach.

S

active formomeprazole

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 Useby Wellmark Members(1.75 M participants in IA/SD)

http://www.wellmark.com/health_improvement/reports/ppi/about.htm

>15% of Wellmark members

>6108 worldwide

19882002

2003

2000

ChiralSwitch

RS

S

http://www.astrazeneca.com/sites/7/archive/Investors/Presentations/2004/astrazeneca-2004-abr-carolyn-fitzsimons-nexium.pdf

…Levine, executive director and develop-ment 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

“Nexium Integrates Clinical, Commercial”

Medical Marketing and Media (Dec, 2003)by Mark Tosh

purplepill.com

Nexium Site

http://www.nexium-us.com/moa/moa.asp (for health professionals)

PROBLEM: Evaluate whether this series of 7 scenes shows superiority of Nexium.

From FDA Approved Nexium Labelhttp://www.fda.gov/cder/foi/label/2004/21153slr015_nexium_lbl.pdf

!(How much would you test?)

60

65

70

75

80

85

90

95

100

Esophagitis % Healed

(RS)-Omeprazole (20 mg)

60

65

70

75

80

85

90

95

100

Esophagitis % Healed

(S)-Omeprazole (20 mg)

60

65

70

75

80

85

90

95

100

Esophagitis % Healed (S)-Omeprazole (40 mg)

Four Clinical Trials

4 Weeks

8 Weeks

4 the dose of Scontained in20 mg of RS !

Nexiumproof.com

NEXIUMPROOF.COM

“If…I told you prescription Nexium heals acid-reflux…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

N

SON

N

OCH3

H3CO

H

N

SON

N

OCH3

H3CO

H

2CF3

Perspectives from a Clinician

Dianne Duffey M.D., FACSSection of Otolaryngology, Department of Surgery

Yale University School of Medicine

Clinical Trials

• design of a clinical trial– Controlling variables– Statistically sound

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• 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

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Duty - Manufacturer

• Are the pharma companies actually designing their studies so that they can make legitimate head-to-head comparisons between competitor compounds?

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Duty - Physician

• evaluate the literature critically

• be able to ascertain the validity of research supporting our choices as clinicians.

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Duty - Patient

• Be an educated consumer

• Direct to patient (DTP) marketing is ubiquitous

• Very effective

• www.fda.gov D. D

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Specialty is Otolaryngology(ENT)

• Laryngopharyngeal Reflux (LPR)– 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

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• 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-to-manage

hoarseness, and 25% to 50% of patients with globus sensation.

Carrau et al; Arch Otolaryngol Head Neck Surg. 2005;131:315-320

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Reflux

• It’s a big problem

• Hence, much money to be made

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LP Reflux

• Treatment: PPI, proton pump inhibitors

• Reality: PPI are FDA approved

http://www.fda.gov/cder/foi/nda/2003/21-229_Prilosec_approv.pdf

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Belafsky et al: ENT-Ear, Nose & Throat JournalSuppl 2,vol 81: September 2002.

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Belafsky et al: ENT-Ear, Nose & Throat JournalSuppl 2,vol 81: September 2002.

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Drug Development

• Only 5 in 5,000 compounds entering preclinical testing make it to human testing

• 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

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FDA APPROVALPrilosec OTC

June 20, 2003http://www.fda.gov/cder/foi/nda/2003/21-229_Prilosec_approv.pdf

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FDA APPROVAL Prilosec OTC (2003)

• “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.”

http://www.fda.gov/cder/foi/nda/2003/21-229_Prilosec_approv.pdf

[omeprazole magnesium delayed-release tablets, 20mg]

[for the treatment of frequent heartburn] D. D

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FDA APPROVALNexium

• Esomeprazole magnesium (Nexium)

– 1) Healing erosive esophagitis;

2) Maintenance of healing of erosive esophagitis; and

3) Treatment of symptomatic gastroesophageal reflux disease (2001)

– 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

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FDA APPROVAL

CLINICAL TRIALS

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Clinical Trials - drug studies in humans

• Phase I

• Phase II

• Phase III

• Phase IV

http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html

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Clinical Trials - drug studies in humans

• Phase I– Healthy volunteers– Endpoint: side effects– Determines metabolism and excretion of drug– N=20-80

• Phase II

• Phase III

• Phase IV

http://www.fda.gov/fdac/special/testtubetopatient/drugreview.html

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Endpoints

• AE - Adverse event, a side effect

• SAE - Serious adverse event; resulted in damage to patient, hospitalization, surgery etc.

• Reported to the FDA during trials D. D

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Clinical Trials - drug studies in humans• 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

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Clinical Trials - drug studies in humans

• Phase I

• Phase II

• 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

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Clinical Trials - drug studies in humans• Phase I

• Phase II

• Phase III

• 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

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Clinical Trials - drug studies in humans

• Phase 0

• Phase I

• Phase II

• Phase III

• Phase IV

Clin Cancer Res 2008; 14(12), 2008

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Clinical Trials - drug studies in humans• Phase 0

– 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

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Reflux Studies

• Sustained resolution (>7days) of heartburn in patients with erosive esophagitis– 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

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• 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)

• Another study: no difference EO 20mg O 20mg (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

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• Approximately 20% to 43% of patients with LPR experience heartburn, and 18% have esophagitis.

• How are we able to use these drugs for LPR?

Carrau et al; Arch Otolaryngol Head Neck Surg. 2005;131:315-320

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“Off-label” Use of Marketed Drugs

• “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

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Duty - Physician

• evaluate the literature critically

• be able to ascertain the validity of research supporting our choices as clinicians.

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Legal Considerationsof Stereochemistry

McBride Disclosure

I have served as scientific consultant or expert witness to a number of pharmaceutical companies including Eisai.

I take Lipitor and served as an expert witness for a generic competitor in a case involving the validity of a Canadian Lipitor patent of Pfizer.

My only connection to AstraZeneca or Omeprazole is as an occasional consumer of Prilosec OTC.

1267-page“Bible” of

Stereochemistry(1994)

8 pp. on“Biological Properties”

Court Rejects Suit Over AstraZeneca Nexium Marketing

Tuesday November 8, 2005, 4:38 PM EST

WILMINGTON, Del. - (Dow Jones Newswire) - A federal court in Delaware Tuesday dismissed a class-action lawsuit that alleged AstraZeneca PLC's (AZN) misleading marketing of Nexium added billions to health-care costs.

U.S. District Judge Sue Robinson rejected the suit brought by the Pennsylvania Employee Benefit Trust Fund on behalf of entities that foot the bill in health- care plans.

Court Rejects Suit Over AstraZeneca Nexium Marketing

According to the health plan paying organizations, the big difference between the two drugs is not effectiveness, but advertising. By selling doctors and patients on the idea that patented Nexium is better than Prilosec, which faced generic competition, AstraZeneca was able to preserve billions in sales.

Judge Robinson said that the courts should defer to the U.S. Food and Drug Administration in weighing the differences between drugs and that since the FDA cleared Nexium's label, the lawsuit could not stand.

2003 Nexium mass-media advertising budget $260M

2005 advertising budget $226M; Sales $5.8B

Back to Chemistry

To test and manufacture Nexium AstraZeneca had to prepare

the single enantiomer

Resolutiona) Pasteur Conglomerate

b) Temporary Diastereomers

Destroy One EnantiomerReact Racemate with Resolved

Chiral Reagent or Catalyst

Prepare only one Enantiomera) Use resolved starting material

b) Use resolved reagent/catalyst

Resolution of Omeprazole

1) Chromatography on SiO2 coated with trisphenylcarbamoylcellulose (1990)

from Ph-N=C=O and Cellulose

Six Chromatograpy Injections 3 mg (+) , 4 mg (-)

Enough to Measure Racemization t1/2 : 1 hr at 75°C , ~100 hr at 37°C

Ph-N=C=O

Not enough for Human Dose (~20 mg)

n

R

R

R

RR

Ph-N C=O

H

R = R

Ph-N C=O

H

(like urea from NH3 + H-N=C=O)

End of Lecture 31Nov. 17, 2010

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