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N
Bu
Cl
Cl
N
N
H
2
C
CH
2
OH
1. HCl
2. KOH
CH
2
OH
N
N
N
N
CPh
3
N
N
K
+
N
N
N
Losartan
An improved and convergent synthesis of losartan depends upon a
Suzuki-coupling reaction.
N
CPh
3
Bu
Cl
N
N
N
N
H
2
C
CH
2
OH
N
+
Suzuki
B(OH)
2
Br
N
Bu
Cl
Cl
N
N
H
2
C
CH
2
OH
1. HCl
2. KOH
N
CH
2
OH
N
N
N
CPh
3
N
N
K
+
N
N
N
Losartan
Inhibition of ACE blocks the formation of angiotensin II which therefore
blocks the renin angiotensin system [26]. Medications that operate by this
principle are in the class termed, ACE inhibitors. ACE is a zinc-containing
enzyme and the zinc ion catalyzes peptide cleavage from angiotensin I to
angiotensin II. ACE inhibitors bind to the zinc cation and therefore inhibit
the cleavage. The first ACE inhibitor was captopril (Capoten
®
, Par Pharma-
ceutical Companies, Inc), a thiol. The discovery of captopril came from an
observation made in the 1960s that an extract of the venom of the Brazilian
viper was a potent ACE inhibitor [27]. The extract was a peptide, not suitable
for oral administration. To find an orally active form, over the next decade,
Squibb spent millions of dollars for research and clinical studies which led
to FDA approval of captopril in the early 1980s. Other thiol-containing ACE
inhibitors are zofenopril and omapatrilat [28].
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