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 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 Companies their 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 alkylation 1 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 Isobutyl Propionic Acid Phenyl Ibuprofen (Advil, Motrin) (S) Active Pain Reliever (R) Inactive Sold as racemate

Sedative Thalidomide (S) Sedative (R) Teratogen Sold as racemate ( ) (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" omeprazole Benzimidazole Pyridine

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 O B 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 (S)-Omeprazole - Stereopair View left eye right eye

(S)-Omeprazole - Stereopair View from X-ray of Ohishi et al 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 Gives Racemate of Course

+ O n Sulfide  Sulfoxide peroxy acid + + H + Gives Racemate of Course ** n d-vacant

Blocking the Proton Pump H+H+ + H+H n ** H + makes  * C=N a lower LUMO omeprazole

n Blocking the Proton Pump - H Enzyme - At 1 < pH < 3 Omeprazole rearranges with t 1/2 ~2 min. ** (“enteric” coating postpones activation during initial passage through acid stomach) Pump enzyme is inactivated, slowing flow of HCl to stomach. Enzyme - OH - + S

Blocking the Proton Pump + At 1 < pH < 3 Omeprazole rearranges with t 1/2 ~2 min. ACHIRAL ! (“enteric” coating postpones activation during initial passage through acid stomach) Should “Chiral Switch” to Single Enantiomer Help Omeprazole? - H + n ** Enzyme OH - + Pump enzyme is tied up. Slows flow of HCl to stomach. S active form omeprazole

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) >15% of Wellmark members >6  10 8 worldwide Chiral Switch RS S

…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. “Nexium Integrates Clinical, Commercial” Medical Marketing and Media (Dec, 2003) by Mark Tosh

purplepill.com

Nexium Site (for health professionals) PROBLEM: Evaluate whether this series of 7 scenes shows superiority of Nexium.

From FDA Approved Nexium Label ! (How much would you test?)

(RS)-Omeprazole (20 mg) (S)-Omeprazole (20 mg) (S)-Omeprazole (40 mg) Four Clinical Trials 4 Weeks 8 Weeks 4  the dose of S contained in 20 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 2 CF 3

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 –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 D. Duffey, with permission

Duty - Manufacturer 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 - Physician evaluate the literature critically be able to ascertain the validity of research supporting our choices as clinicians. D. Duffey, with permission

Duty - Patient Be an educated consumer Direct to patient (DTP) marketing is ubiquitous Very effective D. Duffey, with permission

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 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-to- manage hoarseness, and 25% to 50% of patients with globus sensation. Carrau et al; Arch Otolaryngol Head Neck Surg. 2005;131: D. Duffey, with permission

Reflux It’s a big problem Hence, much money to be made D. Duffey, with permission

LP Reflux Treatment: PPI, proton pump inhibitors Reality: PPI are FDA approved D. Duffey, with permission

Belafsky et al: ENT-Ear, Nose & Throat Journal Suppl 2,vol 81: September D. Duffey, with permission

Belafsky et al: ENT-Ear, Nose & Throat Journal Suppl 2,vol 81: September D. Duffey, with permission

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 D. Duffey, with permission

FDA APPROVAL Prilosec OTC June 20, D. Duffey, with permission

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.” [omeprazole magnesium delayed-release tablets, 20mg] [for the treatment of frequent heartburn] D. Duffey, with permission

FDA APPROVAL Nexium 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) D. Duffey, with permission

FDA APPROVAL CLINICAL TRIALS D. Duffey, with permission

Clinical Trials - drug studies in humans Phase I Phase II Phase III Phase IV D. Duffey, with permission

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 D. Duffey, with permission

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. Duffey, with permission

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 Phase III Phase IV D. Duffey, with permission

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 D. Duffey, with permission

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 D. Duffey, with permission

Clinical Trials - drug studies in humans Phase 0 Phase I Phase II Phase III Phase IV Clin Cancer Res 2008; 14(12), 2008 D. Duffey, with permission

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 D. Duffey, with permission

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” D. Duffey, with permission

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) D. Duffey, with permission

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: D. Duffey, with permission

“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). D. Duffey, with permission

Duty - Physician evaluate the literature critically be able to ascertain the validity of research supporting our choices as clinicians. D. Duffey, with permission

Legal Considerations of 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 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

Resolution a) Pasteur Conglomerate b) Temporary Diastereomers Destroy One Enantiomer React Racemate with Resolved Chiral Reagent or Catalyst Prepare only one Enantiomer a) Use resolved starting material b) Use resolved reagent/catalyst

Resolution of Omeprazole 1) Chromatography on SiO 2 coated with trisphenylcarbamoylcellulose (1990) from Ph-N=C=O and Cellulose Six Chromatograpy Injections  3 mg (+), 4 mg (-) Enough to Measure Racemization t 1/2 : 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 R R Ph-N C=O H R = R Ph-N C=O H (like urea from NH 3 + H-N=C=O)

End of Lecture 31 Nov. 17, 2010 Copyright © J. M. McBride 2009, Some rights reserved. Except for cited third-party materials, and those used by visiting speakers, all content is licensed under a Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0).Creative Commons License (Attribution-NonCommercial-ShareAlike 3.0) Use of this content constitutes your acceptance of the noted license and the terms and conditions of use. Materials from Wikimedia Commons are denoted by the symbol. Third party materials may be subject to additional intellectual property notices, information, or restrictions. The following attribution may be used when reusing material that is not identified as third-party content: J. M. McBride, Chem 125. License: Creative Commons BY-NC-SA 3.0