Chiral drugs

Question 1

Enantiopure drugs

Answer 1

• Potency difference
• Toxicity difference
• TI
• Cost

Question 2

Biological discrimination

Answer 2

• R-isomer of epinephrine fits perfectly into the active site of the enzyme forming an enzyme-substrate complex
• The S-isomer, however, does not fit properly into the active site, therefore, cannot initiate its action

Question 3

Chiral interactions

Answer 3

• Receptor binding
  
  • Enzyme inhibiting
• Protein binding
• Metabolism, enzyme
• All interactions- chiral in principal- all different

Question 4

How to analyse

Answer 4

Question 5

Naming conventions

Answer 5

• The optical isomer are named
  
  • By configuration R and S
  • By configurations D and L
  • By optical activity (+) and (-) or d- and l-

Question 6

S-apomorphine

Answer 6

• S (+) apomorphine- DA antagonist
  
  • D1/D2
  • H down, figure right
• R-apomorphine DA agonist- a racemic mixture

Question 7

L-365,260

CCK-A and CCK-B receptor

Answer 7

• Selectivity towards cholecystokinin receptor
• CCK-A/CCK-B receptor
• Subtype specific interaction
• N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-N’-(3-methylphenyl)urea
• IC50: 2nM for CCK-B receptor, 100 times selective
• S isomer, IC50: 3nM 50 times selective for CCK-A receptor

Question 8

What sparked the change

Answer 8

• 1987 change in FDA regulation
• The inclusion of information of enantiomers in new-drug application NDA
• Phocomelia- shortening of limbs
• Teratogenic drugs: A teratogen is an agent that can disturb the development of the embryo or fetus
  
  • Teratogens halt the pregnancy or produce a congenital malformation (A birth defect)

Question 9

Importance of enantiomers

Answer 9

• The thalidomide tragedy forced drug companies to reconsider enantiomers as separate molecules

Question 10

Thalidomide

Answer 10

• 1960s sedative, morning sickness
• Shortening of limbs
• 1970s in SWS mice teratogenic
• Rodents resistant, poor model
• New zelandwhite rabbits both isomer teratogenic
• Spontaneous racemisation in biological media
• LD50 (Acute toxicity)
• Racemate: 5g/kg
• Isomer: 1.0-1.2g/Kg

Question 11

More toxicity

Answer 11

• Cardioselective beta blocker practolol
• NSAID benoxaprofen
• Anticholinergic Ca antagonist terodiline
• Labetalol induced hepatitis, stopped
• Racemic drug- chiral switch- toxicity up- kill
• Singke enantiomer kill drug

Question 12

Salbutamol

B₂ Adrenergic receptor Agonist

Answer 12

• Salbutamol => mixture of R-salbutamol and SSalbutamol
• Levosalbutamol is the R-enantiomer => active bronchodilator
• Recemic and S-salbutamol
  
  • Induce airway hyper responsiveness
  • Increase senstivity to allergen- toxicity
• Inhalation of levosalbutamol => greater bronchodilation than the equivalent dose of the racemate

Question 13

S-amlodipine

Treatment of HTN

Answer 13

• S-amlodipine => active calcium channel blocker
• R-Amlodipine => inactive as a calcium channel blocker
• Mainly responsible for peripheral oedema
• Toxicity
  
  • S-amlodipine is effective at half life dose of an acetate
  • Incidence of peripheral oedema is negligible

Question 14

Regulatory importance of enantiomers

Answer 14

• The FDA recently recommends the assessments of each enantiomer activity for racemic drugs in the body and promotes the development of new chiral durgsas single enantiomers
• A chiral switch occurs in the pharmaceutical market when a drug made up of 2 enantiomers forms= racemic mixture is replaced with a purified single-enantiomer
• Real benefit or just a marketing tool?

Question 15

Regulatory considerations

Answer 15

1. A pure enantiomer developed from a previously registered racemic drug should be submitted, treated and evaluated as an application for a new drug
2. Therapeutic economic risk/benefit aspects of enantiomer versus racemate must be judged separately for each drug
3. It may not be economically feasible to pay an increased amount for only lightly increase efficacy

Question 16

NSAID

DEXibuprofen

Answer 16

• Inhibition of cyclo-oxygenase activity- S-enantiomer
• 60% of R enantiomer undergoes chiral inversion to the active S-enantiomer
• Chiral Dexibuprofen (1200mg dd) was better than racemate (2400mg dd)
• Highly effective NSAID
• Low adverse effect profile

Question 17

Chiral inversion

Answer 17

Question 18

Ibuprofen (4 steps from benzene)

Answer 18

• Benzene
• FC alkylation, FC acylation
• Nucleophilic Addition
• Reduction followed by hydrolysis

Question 19

Chiral synthesis

Answer 19

• Chiral reduction, Catalyst
• +CO, +Carbon oxide, catalyst
• Shorter used for methanol to acetic acid
• Industrial process
• BASF

Question 20

NSAID: Related propionic acids

Answer 20

• Ibuprofen
  
  • S/R ratio in vitro
  • Inhibition Pg synthesis
  • 160
  • In vivo ratio S/R
  • Writing test, pain threshold
• Naproxen
  *

Question 21

S-Naproxen

Answer 21

• Optical rotation +63- +68.5
• Optical purity 95.5-103.7%
• Chemical purity 99.3%
• Made by chiral synthesis
• Chiral switch, real benefit, same chiral synthesis as ibuprofen

Question 22

Separation ibuprofen

Answer 22

• Buy R and S methylbenzylamine
• Form salt of diastereoisomers
• Separate by crystallisation- Is it max yield
• R/S from R/R diastereoisomers
• Add acid
• Recycle resolving agent
• Collect both enantiomers
• Done by chiral synthesis
• Appreciate issues with the reparation of chiral drugs

Question 23

Separation of enantiomers

Answer 23

• Indirect liquid chromatographic resolution via pre-column derivatization
• Direct resolution of enantiomers using selective chiral stationary phase SP
• Same principle crystallization and chromatography- Separate

Question 24

Naproxen separation using protein based SP

Answer 24

Question 25

Polymer-based stationary phases

Answer 25

• Currently available as cellulose/amylose coated material on the silica support
• Cellulose and amylose unit contains five chiral centres
• Two basic forms
  
  • Derived from cellulose
  • Derived from amylose
• The polymer contains a large number of chiral centre