Chemistry Reference
In-Depth Information
54 million people worldwide [55]. Scientists at Eli Lilly and company recog-
nized that antihistamines had potential as antidepressants. They began synthe-
sizing analogs based upon the antihistamine diphenyhydramine (Benadryl
®
,
Johnson and Johnson) and found fluoxetine to be a selective serotonin
reuptake inhibitor [56]. Eli Lilly scientists believed that the enantiomers
were not significantly different, but in the mid-1990s, the drug company
Sepracor obtained separate patents for use of (
S
)- and (
R
)-luoxetine to treat
migraine and depression, respectively. In 1998, Eli Lilly and Sepracor agreed
to codevelop (
R
)-luoxetine as the single-isomer, side-effect-free version
of Prozac, but the agreement was terminated in 2000 when clinical studies
showed adverse side effectsat high doses not observed with the racemate [57].
N
CH
3
N
O
O
CH
3
CH
3
HCl
F
3
C
Diphenhydramine
Other SSRIs include paroxetine hydrochloride (Paxil
®
, Glaxo SmithK-
line), fluoxamine maleate (Luvox
®
, Abbott), sertraline hydrochloride
(Zoloft
®
, Pfizer), vilazodone hydrochloride (Viibryd
®
, Forest Laboratories),
and citalopram hydrobromide (Celexa
®
, Forest Laboratories).
Fluoxetine hydrochloride
NHCH
3
H
2
N
F
O
O
O
N
OCH
3
CO
2
H
HCl
HCl
CO
2
H
Cl
H
CF
3
Cl
Sertraline hydrochloride
Fluoxamine maleate
Paroxetine hydrochloride
NC
CH
3
CH
3
N
O
O
N
NC
N
NH
2
HBr
H
HCl
O
F
Citalopram hydrobromide
Vilazodone hydrochloride
Paroxetine has two chiral carbons and is administered as a single stereoiso-
mer. Citalopram is one chiral carbon and is administered as a racemic mixture
in Celexa
®
and as the pure S enantiomer in escitalopram oxalate (Lexapro
®
,
Forest Laboratories).
In 2004, 17 years after the introduction of Prozac
®
, duloxetine hydrochlo-
ride (Cymbalta
®
, Lilly) was approved in the U.S. Duloxetine has a chiral
carbon and is the S enantiomer. Duloxetine is a dual reuptake inhibitor of
serotonin and norepinephrine (SSNRI). It is effective against depression and
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