Chiral Drug Design

1. Chiral Drug Design Kate Whitesell 9/26/2007

2. What is chirality? • Isomers • Stereoisomers • Diastereomers • Enantiomers • Racemates

4. Enantiomers • Identical chemical and physical properties in symmetric environments • Except rotation of plane-polarized light • A mixture of equal parts of an isomer and its enantiomer is racemic

5. Importance For Drug Design • The body is chiral • Enantiomers of compounds can react differently in the body, with greatly helpful or harmful outcomes “Nature has a way of knowing how to make things work. Reactions often run in a catalytic mode, and material use, energy, and waste are minimized. Many molecules are chiral, and their unique handedness has both intricate and dramatic influences on how they interact with biological systems.”

6. Thalidomide

7. Thalidomide • German drugmaker Chemie Grünenthal introduced thalidomide, under the name Contergan, to the German market on Oct. 1, 1957 • It was a sedative to treat insomnia as well as to reduce nausea associated with pregnancy. • By 1960, the drug was in more than 20 countries in Europe and Africa. • On Nov. 18, 1961, the German paper Welt am Sonntag reported on a study finding that pregnant women who had been taking thalidomide were giving birth to babies with gross deformities. • "By November 27, Grünenthal had pulled the drug off the market, blaming the sensationalism of the press"

8. Frances Oldham Kelsey • Joined the FDA in 1960 • Richardson-Merrell Inc. submitted a New Drug Application to market thalidomide in the U.S. under the brand name Kevadon. • At the time, the prevailing law was the 1938 Federal Food, Drug & Cosmetic Act • On March 8, 1962, Richardson-Merrell withdrew its drug application, after the effects were widely publicized.

9. 1938 Federal Food, Drug & Cosmetic Act • required proof of safety to be submitted to FDA before a drug could be approved for marketing • did not require demonstration of efficacy • allowed "experimental" use of drugs while approval was being sought, which meant that a drug could be distributed widely before it was approved

10. Thalidomide sparked major changes for the FDA ”’the drug approval process was under considerable criticism, particularly the quality of the scientific data submitted in New Drug Applications and the lack of an efficacy requirement,’ according to Kelsey, writing in the 1996 annual report of FDA's Office of Compliance. ‘The nature and magnitude of the thalidomide disaster,’ she wrote, spurred the swift passage of legislation addressing the shortcomings of the 1938 law that had been sitting in Congress before the disaster. Known as Kefauver-Harris Drug Amendments, they were signed into law by President John F. Kennedy in October 1962.”

11. Impact on Today • Today it is often easier to submit single enantiomeric chiral drugs rather than racemic chiral drugs • Old racemates are often reassessed as single enantiomers • Synthesis, separation and analysis of chiral compounds has advanced greatly, and is highly sought

12. Potential advantages of single enantiomer products • Less complex, more selective pharmacodynamic profile • Potential for an improved therapeutic index • Less complex pharmacokinetic profile • Reduced potential for complex drug interactions • Less complex relationship between plasma concentration and effect

13. Some differences: • “the mean daily dose … was reduced by approximately one third compared to the racemate” • “the cardiotoxicity of the drug appears to be predominantly associated with the (R)-enantiomer” • “significantly reduced negative inotropic effect (approximately half) was observed with the single enantiomer compared to the mixture” • “between 130 and 160 fold more potent than the (R)-enantiomer” • “faster onset of action, reduction of side effects and improved tolerability profile” • “the S-enantiomer being effectively inactive”

14. Not Perfect • Maybe no advantage • Unexpected adverse reactions • Sotalol, (+) is 14 to 50 fold less active, but enantiomers are equipotent in antiarrhythmic activity. Increased mortality in test group compared to placebo and racemates. • Highly unlikely that a drug company will develop racemates of “failed” single enantiomer

15. SEPARATION Preparative chiral chromatography Cheaper despite waste Applicable to most small chiral molecules Crystallization of diastereomeric salts SELECTIVITY Chiral pool A lot of catalysis Enantioselective processes Conversion of enantiomers Current Chiral Methods: cost and time “Speed is essential, and you don’t always have the luxury of trying to come up with the best synthesis”

16. Despite Cost • 2006, 80% of small-molecule drugs approved by the FDA were chiral • 75% were single enantiomers • About 200 chiral compounds should enter the market each year • The field of asymmetric synthesis is expanding rapidly, 50% of chiral drugs use chiral technologies • Due to FDA policy as of 1994, decision to create racemic mixture must be justified in quality, safety, and efficacy, may be case-by-case

17. Sepracor • Located in Marlborough, MA • Founded in 1984, first major drug in 2000 • Lunesta, Xopenex, Xopenex HFA, Brovana • Schering-Plough for CLARINEX; Sanofi-Aventis for ALLEGRA; and UCB Pharma for XYZAL /XUSAL™. • Focus on treatment of respiratory and central nervous system disorders • Insomnia, asthma, chronic obstructive pulmonary disease, depression

18. Mission “Sepracor Inc. is a research-based pharmaceutical company dedicated to treating and preventing human disease by discovering, developing, and commercializing innovative pharmaceutical products that are directed toward serving unmet medical needs. Our drug development program has yielded a portfolio of pharmaceutical products and candidates with a focus on the treatment of respiratory and central nervous system disorders. Our commercialization efforts are carried out by our U.S.-based primary care and specialty-oriented sales force, as well as through out-licensing partnerships.”

19. (R)-fluoxetine There was a recent termination of the licensing agreement between Eli Lilly and Sepracor, due to which Sepracor received $23 million of what was supposed to be $90 million. -The cost for Sepracor is considered to be lower than that of other drug companies - possiblity of success is supposedly higher - maybe less paperwork

20. Levalbuterol • XOPENEX is (R)-enantiomer of albuterol • Albuterol is aβ2-adrenergic receptor agonist • short-acting bronchodilator for reversible obstructive airway disease, such as asthma. Levalbuterol caused fewer reported side effects than albuterol. Levalbuterol vs albuterol: Total percent reporting symptoms, 22% vs 78%. Tremor, 22% vs 78%. Nervousness, 0% vs 56%. Palpitations, 0% vs 56%. Tachycardia, 0% vs 44%.

21. Worth the risk? As of July 1, Medicare cut reimbursement levels for Xopenex after the Centers for Medicare & Medicaid Services applied the same reimbursement code to Xopenex and to generic albuterol Sepracor stock fell over 54%. Sepracor, which is based in Marlborough, Massachusetts, brought down its 2007 revenue forecast to between $1.23 billion and $1.3 billion from a previous forecast of between $1.43 billion to $1.49 billion.

22. Conclusion Chiral drugs are very important, in terms of efficacy and applications in the human body, but they are not a universal solution, and there are still many risks in their development. “Nature has a way of knowing how to make things work. Reactions often run in a catalytic mode, and material use, energy, and waste are minimized. Many molecules are chiral, and their unique handedness has both intricate and dramatic influences on how they interact with biological systems.”