Probably the most well-known and tragic example of a drug in which the distomer
causes serious side effects is ‘Thalidomide’, which was administered as a racemate in
the 1960s. At that time it was not known that the sedative effect resides in the (R)enantiomer, but that the (S)-counterpart is highly teratogenic [79].
10
As a consequence, racemates of pharmaceuticals and agrochemicals must be
regarded with great caution. Quite astonishingly, 89% of the 537 chiral synthetic
drugs on the market were sold in racemic form in 1990, while the respective situation
in the field of pesticides was even worse (92% of 480 chiral agents were racemic)
[80, 81]. Although at present many bioactive agents are still used as racemates for
economic reasons, this situation is constantly changing due to increasing legislation
pressure [82]. In 1992, the US Food and Drug Administration (FDA) adopted a longawaited policy on the issue of whether chiral compounds may be applied as racemic
mixtures or as single enantiomers [83–85]. According to these guidelines, the
development of racemates is not prohibited a priori, but must undergo rigorous
justification based on the separate testing of individual enantiomers. Consequently,
single enantiomers are preferred over racemates, which is indicated by the fact that
the number of new active pharmaceutical ingredients (APIs) in racemic form
remained almost constant from 1992 to 1999, but they almost disappeared from
2001 onwards, going in hand with the doubling of numbers for single enantiomers
[86, 87]. For agrochemicals the writing is on the wall: the current climate of
‘environmentality’ imposes a pressure for the development of enantiopure agents.
Overall this has caused an increased need for enantiopure compounds [88, 89].
NH 2
O
NH 2
HO 2 C
H 2 N
O
N H 2
COOH
O
O
NH 2
HO 2 C
SH
NH 2
CO 2 H
HS
sweet
bitter
Asparagine
anise scent
caraway scent
Carvone
Penicillamine
antiarthritic
toxic
S -Enantiomer
R -Enantiomer
Scheme 1.1 Biological effects of enantiomers
10 According to a BBC-report, the sale of rac-thalidomide to third-world countries has been
resumed in mid-1996!
6
1 Introduction and Background Information
causes serious side effects is ‘Thalidomide’, which was administered as a racemate in
the 1960s. At that time it was not known that the sedative effect resides in the (R)enantiomer, but that the (S)-counterpart is highly teratogenic [79].
10
As a consequence, racemates of pharmaceuticals and agrochemicals must be
regarded with great caution. Quite astonishingly, 89% of the 537 chiral synthetic
drugs on the market were sold in racemic form in 1990, while the respective situation
in the field of pesticides was even worse (92% of 480 chiral agents were racemic)
[80, 81]. Although at present many bioactive agents are still used as racemates for
economic reasons, this situation is constantly changing due to increasing legislation
pressure [82]. In 1992, the US Food and Drug Administration (FDA) adopted a longawaited policy on the issue of whether chiral compounds may be applied as racemic
mixtures or as single enantiomers [83–85]. According to these guidelines, the
development of racemates is not prohibited a priori, but must undergo rigorous
justification based on the separate testing of individual enantiomers. Consequently,
single enantiomers are preferred over racemates, which is indicated by the fact that
the number of new active pharmaceutical ingredients (APIs) in racemic form
remained almost constant from 1992 to 1999, but they almost disappeared from
2001 onwards, going in hand with the doubling of numbers for single enantiomers
[86, 87]. For agrochemicals the writing is on the wall: the current climate of
‘environmentality’ imposes a pressure for the development of enantiopure agents.
Overall this has caused an increased need for enantiopure compounds [88, 89].
NH 2
O
NH 2
HO 2 C
H 2 N
O
N H 2
COOH
O
O
NH 2
HO 2 C
SH
NH 2
CO 2 H
HS
sweet
bitter
Asparagine
anise scent
caraway scent
Carvone
Penicillamine
antiarthritic
toxic
S -Enantiomer
R -Enantiomer
Scheme 1.1 Biological effects of enantiomers
10 According to a BBC-report, the sale of rac-thalidomide to third-world countries has been
resumed in mid-1996!
6
1 Introduction and Background Information