Chiral Drug Design

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Chiral Drug Design
History Importance of Chiral Drug Design
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Weve been talking about Stereoisomers.

• Isomers
• Constitutional Isomers
• Stereoisomers
• Cis vs trans (EZ)
• Enantiomers
• Diastereomers
• Meso Compounds (later next week)

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Molecules with Asymmetric Centers

• An sp3 atom, usually carbon, with 4 UNIQUE groups
  attached!
• Asymmetric center chiral center

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If a molecule has at least one chiral center

• It can be an optically active molecule.
• -Enantiomers
• -Diastereomers
• Meso compounds are optically INACTIVE.

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Optically ActiveRotates the plane of polarized
light clockwise () or counterclockwise (-)

• (/- have no bearing on the type of asymmetric
  center we will explain types of chiral centers
  in a minute!)

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Chiral centers have handedness

• Enantiomers are non-superimposable mirror images!

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Enantiomers

• Chiral Centers are Complete Opposites (R/S, S/R,
  etc)
• R/S determination after slide show!
• Identical chemical and physical properties
• Except rotation of plane-polarized light

(S)-Alanine (left) and (R)-alanine (right)
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How are Diastereomers Different?

• Have at least 2 chiral centers partially
  opposite chirality.
• Chiral centers are PARTIAL opposites
• R,S R, R
• R, S S, S
• Have DIFFERENT chemical physical properties.

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(-)Threose (-) Erythrose
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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.
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1957 Thalidomide (Racemic Mixture)
The two enantiomers of thalidomideLeft
(S)-thalidomide Right (R)-thalidomide
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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"

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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.

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Frances helped uncoverThe S-enantiomer of
thalidomide, caused the teratogenic effects (body
mutations etc). The once believed "safe"
R-isomer can be converted to the teratogenic
isomer once metabolized human body.
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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

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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.
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Impact on Today

• Old racemic mixture drugs are often reassessed as
  single enantiomers
• Synthesis, separation and analysis of chiral
  compounds has advanced greatly, and is highly
  sought (chromatography)

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Some Statistics

• 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

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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

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Levalbuterol

• XOPENEX is (R)-enantiomer of albuterol
• short-acting bronchodilator for reversible
  obstructive airway disease, such as asthma.
• Levalbuterol caused fewer reported side effects
  than albuterol.
• Effects Levalbuterol vs albuterol
• Tremor, 22 vs 78.
• Nervousness, 0 vs 56.
• Palpitations, 0 vs 56.
• Tachycardia, 0 vs 44.

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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.
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• So lets continue practicing!!!!
• Drawing our Perspective Fischer (bow-tie on a
  skelton) Projections
• Identifying type
• of Chirality