Drug Chirality : Past , Present & Future (?)

1
Drug Chirality Past , Present Future (?)

• Andrew J. Hutt.
• Department of Pharmacy,
• Kings College London.

2

• Stereochemistry
• Concerned with the three dimensional spatial
  arrangement of the atoms within a molecule.
• Stereoisomers
• Compounds with the same molecular
  connectivity but differ in the spatial
  arrangement of their constituent atoms or groups.
• Enantiomers
• Stereoisomers which are non-superimposable
  mirror images of one another.
• Diastereoisomers
• Stereoisomers which are not enantiomeric.

3
Chiros Greek Handed
4
Stereoisomers of Ibuprofen
5
Stereogenic S P centres
6
Stereoisomers of Phenylpropanolamine
7
Phenylpropanolamine UK Confusion

• Independent risk factor for hemorrhagic stroke in
  women1
• Withdrawn in the USA (FDA, Oct. 10, 2000)
• ()-norpseudoephedrine in European
  preparations(?)-norephedrine in North
  America(Martindale 32nd Pharm J, Nov. 11, 2000)
• (?)-norephedrine in USA and Europe structure of
  norpseudoephedrine presented in the British
  Pharmacopoeia 2000 (Pharm J, Dec. 2, 2000)

1Kernan WN, et al. N Engl J Med.
20003431826-1832.
8
Methaqualone enantiomers
9
(No Transcript)
10

• Differences between stereoisomers are hard to
  detect normally, but become much more marked in
  a chiral environment

11
Chiral Biological Macromolecules

• Proteins
• Enzymes
• Structural elements of membranes
• Receptors
• Carbohydrates
• Nucleic acids
• Chiral building blocks of L-amino acids and
  D-carbohydrates.

12
Helical structures
13
Pasteur Tartaric Acid

• Physically separation of enantiomorphous
  crystals sodium ammonium salts.
• Biologically fermentation using Penicillum
  glaucum ()-enantiomer, carbon source leaving
  the (-)-enantiomer.
• Chemically resolution of diastereoisomeric
  salts using the optically pure base cinchonicine.

14
Chirality Biology

• Piutti (1886) - ()-asparagine has a sweet taste
  while the natural (-)- enantiomer is insipid.
• Pasteur (1886) - --- this difference due to the
  presence of an optically active substance in the
  nervous mechanism of taste --
• Regarded as the first mention of
  stereoselectivity of a receptor (Holmstedt,
  1990).

15
Arthur R. Cushny Chiral Pharmacology

• (-)-Hyoscyamine almost exactly twice as active as
  atropine ()- hysocyamine (1904).
• (-)-Adrenaline twice the potency of
  ()-adrenaline as a vasoconstrictor (1908)
  (-)-enantiomer 12-15 fold more potent than
  ()-adrenaline on sympathetic vessels (1909).
• Biological Relations of Optically Isomeric
  Substances (1926)

16
Cushny Chiral Pharmacology

• Believed that the receptor was chiral and
  combined with the enantiomers of the drug to
  produce diastereoisomeric drug receptor
  complexes.
• ---- difference in action lies not in the
  facility with which the chemical combination is
  formed, but in the physical characteristics of
  the resultant compound (Cushny, 1926).

17
Easson Stedman ModelThree Point Interaction.
18
Easson Stedman Prochiral Analog Two Site
Interaction.
19
Ogston Prochirality

• Three point attachment Model to rationalise the
  observed stereoselectivity in the enzymatic
  transformation of symmetrical, prochiral,
  substrates.
• A A are identical enantiotopic if A is the
  catalytic site then A, but not A will undergo
  transformation.
• Static Model.

20
Rocking Tetrahedron Model

• Dynamic Model.
• Substrate binds at two interaction sites.
• A A occupy overlapping, identical volumes.
• Enantioselectivity is dependant on the
  orientation of A A to the catalytic sites X or
  Y.
• Attack from X, no selectivity from Y potentially
  highly selective/specific.

21
Four Location Model

• Isocitrate dehydrogenase involved in the
  tricarboxylic acid cycle, converts
  ()-(1R,2S)-isocitrate to 2-oxoglutarate carbon
  dioxide.
• In the presence of Mg2 the enzyme binds
  ()-(1R,2S)-stereoisomer, the substrate in the
  absence of Mg2 the (-)-(1S,2R)-enantiomer (not a
  substrate, weak inhibitor) binds.

22
Four Location Model
23
Chiral Recognition Current View

• Complex formation between the selector (receptor,
  enzyme) and selectand (drug, substrate) such that
  there is a diastereomeric relationship.
• In the absence of other constraints, imposing a
  specific orientation of the selector to the
  selectand, a minimum of four contact points are
  required.
• Thus the Easson-Stedman Ogsten Models are
  specific cases of a Four Point Interaction.

Bentley (2000)
24
Chiral Pharmaceuticals the 1980s 90s

• During the Golden Age of drug discovery
  development, the 1950s to the 1970s,
  stereochemistry was largely ignored resulting in
  approximately 25 of pharmaceuticals being
  marketed as racemates by the 1980s.
• Advances in chemical technology associated with
  synthesis, analysis and preparative scale
  separation of chiral molecules resulted in a
  change in philosophy with respect to drugs.
• Facilitated the Pharmacological evaluation of
  single stereoisomers increasing concern with
  respect to safety issues Regulatory interest.

25
Drug Chirality The 1980s
Non chiral 6
Sold as single isomer
Naturalsemisynthetic 475
461
Chiral 469
Sold as racemate
Drugs 1675
8
Sold as single isomer
Non chiral 720
58
Synthetic 1200
Chiral 480
Sold as racemate
422
26
Pharmacodynamic Considerations

• Stereoselectivity of drug action has been known
  for a number of years.
• Many natural ligands are chiral, eg,
  transmitters, hormones, etc.
• Additional Terminology
• Eutomer enantiomer with higher
  affinity/activity.
• Distomer enantiomer with lower
  affinity/activity.
• Eudismic Ratio Ratio of the Eutomer/Distomer
  affinities or activities.
• Eudismic Ratios of 100 to 1000 fold are not
  uncommon.

27
Eudismic Ratio

• Terminology applies to a particular activity of a
  drug.
• Dual action drug the Eutomer of one activity may
  be the Distomer for another.
• Propranolol S-enantiomer 40-100 fold more potent
  than the R- as a ß-adrenoceptor antagonist
  similar activity with respect to their membrane
  stabilising properties.
• Eudismic Ratios may also vary with receptor
  subtypes.
• Noradrenaline ER (R/S) a1, 107 a2, 480.
• a-Methylnoradrenaline ER (1R,2S/1S,2R) a1,
  60a2, 550.

28
Pharmacodynamic Complexity

• Activity resides in a single enantiomer
  (S)-?-Methyldopa
• Both enantiomers have similar activity
  Flecainide
• Both enantiomers marketed with different
  indications Propoxyphene
• Enantiomers have opposite effects Picenadol
• One enantiomer antagonizes the side effects of
  the other Indacrinone
• Activity resides in one or both enantiomers,
  adverse effects predominantly associated with one
  Ketamine
• Racemate provides a superior therapeutic effect
  than either individual enantiomer Dobutamine.

29
Pharmacokinetics

• Absorption - active transport.
• Distribution - active/selective uptake, protein
  binding,
• selective tissues
  distribution.
• Metabolism - numerous examples
• Excretion - active secretion or reabsorption

30
Enantiomeric Differences in Pharmacokinetic
Profile
31
Drug Stereochemistry

• Relatively little is known concerning the
  significance of
• Route of administration, dose, formulation
• Drug interactions
• Age
• Gender
• Disease
• Genetics

32
Verapamil Dose-response curve route of
administration
33
Propranolol Potency and route of administration.
34
Pharmacokinetics

• As a result of stereoselectivity in drug
  disposition a pair of enantiomers rarely exist as
  11 mixtures in biofluids.
• Estimation of pharmacokinetic parameters,
  development of Models and/or concentration-effec
  t relationships based on total drug are of
  limited value and potentially misleading.
• Stereochemistry Sophisticated Nonsense.
• Prof E.J.Ariens (1984)

35
Body of Evidence

• Im not sure I get it, Marino said, rubbing his
  eyes. How can compounds be the same but
  different?
• Think of dextromethorphan and levomethorphan as
  identical twins, I said. Theyre not the same
  people, so to speak, but they look the same
  except one is right-handed and the other
  left-handed. One is benign, the other strong
  enough to kill. Does that help? Dr Kay
  Scarpetta
• Patricia Cornwell, 1991

36
(No Transcript)
37
Use of Racemates

• Isomeric ballast
• Clean drugs
• Polypharmacy

38
FDA

• The Agency is impressed by the possibility that
  the use of single enantiomers may be
  advantageous (1) by permitting better patient
  control, simplifying dose-response relationships
  (2) by reducing the extent of interpatient
  variation in drug response.

39
Potential Advantages of Single Isomer Products

• Less complex and more selective pharmacological
  profile
• Potential for an improved therapeutic index
• Less complex pharmacokinetic profile
• Reduced potential for complex drug interactions
• Less complex relationships between plasma
  concentration and effect

40
Racemates vs Enantiomers

• No requirement from any regulatory authorities
  for marketing single isomers
• Choice of stereoisomeric form must be justified
  on scientific grounds

41
Handed Headlines (1)

• S. Mason (1984)
• The left hand of nature.
• New Scientist 10110-14.
• D. Matterson (1991)
• Through the chemical looking glass.
• New Scientist 13235-39.
• I. Amato (1992)
• Looking glass chemistry.
• Science 256964-966.

42
Handed Headlines (2)

• N. Moran
• Drug firms sort their lefts from their
  rights.
• Independent on Sunday (7/11/1993).
• N. Hawkes
• Lateral thinking.
• The Times Magazine (5/6/1993).
• T. Lister
• Mirror images.
• Guardian (11/1/1994).

43
Thalidomide
44
Thalidomide Enantiomers

• Both are sedative in the mouse, only
  (S)-thalidomide is teratogenic.
• Mouse is a poor model for teratogenicity.
• Both are teratogenic in NZW rabbits.
• Enantiomers undergo rapid racemization in vivo
  and in vitro.
• In man following administration of the R- and
  S-enantiomers ca 25 and 43 of the total AUC is
  due to the alternative stereoisomer.

45
Strategies for the Synthesis Preparation of
Chiral Compounds

• Use of optically pure starting materials
• Carbohydrates, amino acids, alkaloids,
  steroids, other natural products.
• Asymmetric Synthesis
• Chiral catalysts.
• Biological methods
• Microorganisms and enzymes designer enzymes
  (site directed mutagenesis).
• Separations
• Classical resolutions Simulated Moving Bed
  (SMB) Supported Liquid Membrane.

46
Value of Chiral Products Approaches
Growth rate 11.4
CEN
47
Chiral Switch

• Switch from a racemic to single enantiomer
  Active Pharmaceutical Ingredient is key to
  managing the life cycle, as well as improving the
  efficacy, of racemic drugs.
• CEN 2004

48
Chiroscience UK

• Dexketoprofen (Keral) 1996
• Levobupivacaine (Chirocaine) 1998
• Sepracor USA
• Levalbuterol (Xopenex, Xopenex HRA)
• Eszopiclone (Lunesta, 2005)
• Levocetirizine (Xyzal, Xusal)
• Arformoterol (Brovana, 2007)
• (S)-Amlodipine (USA Phase II clinical trials
  India, marketed)

49
Chiral Switch Patents

• One patent for a single isomer was refused
  because of a statement in a textbook that the
  biological effects of enantiomers can differ
• Another refused because the discovery of the
  effect was not an inventive step but obvious
  from prior art
• Hence, patentability of single enantiomers is
  based on inventiveness not obvious from prior
  art.
• A patent on the racemate is a patent on the
  chemical formula without specifying
  stereochemistry.
• CEN 81 (2003) 56

50
Enantiomeric Patents Inhalational Anaesthetics

• US Patents 5,114,714 5,114,715
• R-enantiomers of isoflurane and desflurane are
  better than the racemate
• S-enantiomers of isoflurane and desflurane are
  better than the racemate
• Essentially the only difference in the Patents
  are the R- and S- descriptors.

51
Chiral Switch Not a New Idea

• Penicillamine treatment of Wilsons disease
  animal toxicity weight loss, intermittent fits,
  death in rats L gtgt D mutagenicity L gt D Optic
  neuritis with racemate in man, drug withdrawn
  (USA).
• Dopa L-dopa decarboxylated to yield dopamine
  side effects nausea, vomiting, anorexia, mental
  effects,involuntary movements, granulocytopenia.
• Norgestrel progestogen oral contraception.

52
Racemate to Enantiomer Racemic or Chiral
Switches

• Drug Name Class Approval Status
• Dexfenfluramine Anoretic Withdrawn
• Levofloxacin Antimicrobial Japan, UK, USA
• Dilevalol ?-blocker Development stopped
• Dexibuprofen NSAID Austria (1994), Switzerland,
  EU (2005)
• Dexketoprofen NSAID Spain, UK
• Levobupivacaine Local anesthetic UK
• (S)-Ketamine Anesthetic Germany
• Esomeprazole H-pump inhibitor UK, USA
• (R)-Salbutamol ?2-agonist USA
• (R)-Fluoxetine Antidepressant Development stopped
• Cisatracurium Neuromuscular blockade UK,
  USALevocetirizine Antihistamine UK,
• (R,R)-Methylphenidate ADHD USA
• Escitalopram Antidepressant UK, USA
• (S)-Amlodipine Dihydropyridine India
• Eszopiclone Insomnia USA (April 2005)
• Arformoterol ?2-agonist USA (April 2007)
• Armodafinil Antinarcoleptic USA (Approvable
  letter, April 2007)

53
Chiral Switch Commercial Aspects

• Advantage over de novo drug design chance of
  success that much greater costs lower.
• Omeprazole / Esomeprazole (R,S) sales 2001, 5.6
  billion combined sales (R,S) (S) 2002 6.6
  billion.
• Patents for Nexium give AZ more than 20 years of
  protection on the same molecule, omeprazole.
• Citalopram / Escitalopram (R,S) sales 2002, 1.1
  billion (S) last three months of 2002, 81
  million.
• FDA does not consider single enantiomers of
  approved drugs as NCE and marketing exclusivity
  for (S) 3 years.

54
Chiral Switch Problems

• Labetalol combined a- and ß-adrenoceptor
  antagonist mixture of four stereoisomers, two
  pairs of enantiomers a- and ß-activity resides
  in the S,R- and R,R-stereoisomers respectively.
• Dilevalol (R,R)-labetalol development stopped
  due to hepatotoxicity in a small number of
  patients.
• Cost Schering 100 million (Scrip 1543).

55
Chiral Switch Problems

• Sotalol racemic, nonselective ß-adrenoceptor
  antagonist with Class III antiarrhythmic
  activity.
• (-)- enantiomer 14 to 50 fold more potent as a
  ß-blocker equipotent as antiarrhythmic.
• SWORD trial (Survival With Oral d-Sotalol)
  evaluated in patients with depressed ventricular
  function following myocardial infraction.
• Study terminated following recruitment of less
  than 50 of the intended 6,400 patients due to
  increased mortality in tratment group (5)
  compared with placebo control group (3.1)
  Lancet 1996.

56
Chiral Switch Problems

• (R)-Fluoxetine development as single isomer
  Sepracor Licensing agreement with Lilly.
• More predictable pharmacology, shorter washout
  period reduction in accumulation increased
  flexibility of treatment.
• But at the highest dose level examined small but
  significant increase in QTc interval development
  stopped.
• Sepracor received 23 million of what was to have
  been a 90 million deal Sepracor stock value
  fell by 28 (Chem Eng News 2000).

57
Chiral Switch Problems

• Dexfenfluramine / Fenfluramine anoretic agent
  racemic drug had been available for 25 years.
• Association with valvular heart disease initially
  reported for the combined use of
  fenfluramine-phentermine
• (fen-phen combination ) in the USA.
• Also, rare but serious risk of pulmonary
  hypertension.
• Both single enantiomer and racemate voluntarily
  withdrawn.
• NEJM, 1997 Current Problems in
  Pharmacovigilance, 1997

58
Chiral Switch Reversed!

• Methadone used as maintenance therapy in the
  management of opioid dependence.
• R-enantiomer 50 fold more potent analgesic
  compared to (S)-methadone.
• Racemate used in the majority of countries but
  R-enantiomer used in Germany.
• Decrease costs, replaced by a double dose of the
  racemate.
• Result decrease in the serum concentration/dose
  ratio for the active enantiomer some patients
  experienced withdrawal symptoms, required dose
  adjustment.

59
New Chemical Entities Assessed by the UK
Medicines Control Agency (MCA/MHRA) between
1996-2000
Non-chiral 2
Naturalsemisynthetic 19
Single isomer 16
Chiral 17
NCEs 95
Racemate 1
Non-chiral 31
Synthetic 76
Single isomer 30
Chiral 45
Racemate 15
Shah Branch, 2003.
60
The Future - Predictions

• US Adopted Names (USAN).
• The Council of the USAN assigns generic names to
  all drugs that have entered clinical trails and
  therefore have commercial potential.
• Drugs with proven benefit reach the market a few
  years later.
• Nomenclature is regarded as an indicator of the
  pharmaceutical pipeline.

61
Recent Chiral Trends USA

• In 2006, 80 of small molecule drugs approved by
  the FDA were chiral and 75 were single
  enantiomers.
• CEN August 2007

62
Analysis of USAN Adoption Records
63
Chiral Switches

• The concept that a single enantiomer of a chiral
  drug may be preferable to a racemic mixture is
  intellectually appealling. However, in most
  instances this strategy has not been demonstrated
  to confer any clinical advantage.
• Therapeutics Letter, June-Sept 2002
• BC Ministry of Health

64
Chiral Switches

• Esomeprazole --- at equivalent doses offers no
  therapeutic advantage over other PPIs.
• Escitalopram Current knowledge provides no
  reason to expect a clinically significant
  advantage over the racemate.
• (R)-Albuterol ((R)-Salbutamol) --- it offers no
  demonstrated clinical advantage.
• Therapeutics Letter, June-Sept 2002
• BC Ministry of Health

65
Chiral Switches

• Levocetirizine To date, there are no studies
  that compare these drugs for the treatment of hay
  fever.
• There is little evidence to confirm whether in
  practice, third generation antihistamines confer
  any benefit over those from the second
  generation.
• MeReC Bulletin 14(5) 2004
• The National Prescribing Centre

66
Chiral Switches

• Unfortunately there seems to be a dearth of
  appropriate head to head studies that would allow
  prescribers the opportunity to decide whether any
  of these potential advantages can be
  substantiated for any particular drug.
• London New Drugs Group
• APC/DTC Briefing
• --- escitalopram is a well-tolerated,
  efficacious antidepressant of the SSRI class
  which may also have application in anxiety
  disorders. However, concrete data is lacking
  demonstrating the benefits of this new
  antidepressant over the others currently
  marketed, including the racemic product.
• Canadian Coordinating Office for Health
  Technology Assessment
• January 2003

67
Esomeprazole

• Efficacy and safety of Esomeprazole compared
  with omeprazole in GERD patients with erosive
  esophagitis A randomized controlled trial.
• Gastroesophageal Reflux Disease 425 patients
  163 centres.
• Compared once daily doses of 40 mg S- with 20 mg
  racemate.
• Healing rates at 4 weeks 81.7 S- vs 68.7 Rac
  at 8 weeks 93.7 S- vs 84.2 Rac.
• Conclusion Esomeprazole demonstrates
  significantly greater efficacy than omeprazole
  tolerability and safety of esomeprazole are
  comparable to that of omeprazole.
• Am J Gastroenterol 96 (2001) 656-665.

68
Chiral Switches

• Differences between single enantiomers and
  racemates are likely to become the focus for
  aggressive promotion of the new entity.
  Regulatory authorities and independent sources of
  drug information need to be provided with good
  evidence, from well-conducted clinical trials and
  appropriate pharmacoeconomic studies, that chiral
  switches have advantages for the prescriber and
  the consumer.
• Australian Prescriber 27, 47-49 (2004)

69
Chiral Switch Problems USA

• If insurers are less willing to pay the added
  cost fewer may be developed
• Relative merits have been debated, benefits may
  not justify the added costs
• Esomperazole vs Omeprazole in Chicago area Cost
  30 days supply
• Omeprazole 20mg 22
• Esomeprazole 40mg 155
• Esomeprazole 20mg 145
• Unscientific, no indication of clinical outcome.
• AMA 3/11/05

70

• Escitalopram (Lexapro)
• Forest Lundbeck suing Ivax (Teva Pharmaceutical
  Industries) for patent infringement.
• Ivax argue that single-isomer patents are
  invalid and only the original substance can be
  patented.
• Scrip No 3140 17/3/06
• Esomeprazole (Nexium)
• AZ filed a lawsuit against Teva alleging
  infringement of patents.
• Teva intends to market a generic version.
• Scrip No 3140 17/3/06

71
How would you like to live in Looking-Glass
House, Kitty? I wonder if theyd give you milk
in there? Perhaps Looking-glass milk isnt good
to drink-
Lewis Carroll Through The Looking-Glass and What
Alice Found There
72
(No Transcript)