FLUORINE IN THE LIFE SCIENCE INDUSTRY
124
CHIMIA 2004, 58, No. 3
exchange of the p-fluoro-phenyl substituent
against a p-trifluoromethyl phenyl sub-
stituent accompanied by a shortening of the
spacer (3) resulted in another increase of
potency. The introduction of fluorine at the
bis-benzylic bridge (rac-4) led to a further
improvement and the exchange of the iso-
propyl versus a cyclopentyl moiety pro-
duced a highly potent CETP inhibitor. In its
enantiomerically pure form lead candidate
5 already has an inhibitory activity at CETP
of IC50= 13nM.
Fig. 1
3. First Generation CETP-Inhibitors
However, the metabolic stability of this
lead compound was insufficient. During the
later phase of the project the optimization
of this and other parameters was addressed
in order to meet the requirements for a de-
velopment candidate. The metabolism of
the primary alcohol was tackled by rigidifi-
cation in a bicyclic structure (Fig. 3). Al-
though alkyl replacement of the right hand
p-F-phenyl substituent (rac-6) led to a com-
plete loss of activity the rigidification of the
alcohol group through cyclization gave a
promising result, albeit at the expense of in-
troducing another stereogenic center: The
anti-diastereomer displays an IC50 of 100
nM as a racemate (rac-7). Based on this
new bicyclic core structure an intensive
structure–activity screening by chemical
derivatization was performed (Fig. 4). The
para-fluoro substitution at the phenyl-sub-
stituent, commonly introduced to prevent
metabolic para-hydroxylation, improves
potency by a factor of three. The fluorine
substituent in the bis-benzylic bridge leads
to the most potent inhibitors as shown in
Fig. 4. Another unique substituent was the
trifluoromethyl group in p-position of the
phenyl substituent. Probably due to optimal
size and lipophilicity no other substituent
gave a better result regarding potency. A
breakthrough was achieved by methyl-sub-
stitution at the cyclohexyl moiety in 1,3 po-
sition to the hydroxy group (Fig. 4).
To avoid another stereogenic center a
geminal dimethyl compound was prepared
and proved to be equally active. The enan-
tiomerically pure compound 8 was chosen
as the first development candidate for
CETP-inhibition (Fig. 5). The configura-
tion of the alcoholic carbon center is crucial
for high potency as isomer 9 demonstrates.
The inversion of the fluorine bearing center
as in compound ent-9 leads to a more than
twofold decrease in activity.
Fig. 2
via the biotin-streptavidin system. If a successful optimization delivered a highly
transfer of cholesteryl ester to the LDL par- potent lead compound 5. Fluorine substi-
ticle has taken place the radioactivity is lo- tution played a key role in this process
cated in the vicinity of the fluoro-bead. This (Fig. 2).
In order to provide sufficient quantities
of material a technically feasible synthesis
was established for candidate 8 (Scheme 1).
After preparation of enamine 10 the reac-
tion sequence starts with an unsymmetrical
Hantzsch-dihydropyridine synthesis of
compound 11, followed by an oxidation to
results in a light-signal which is detected in
A
significant improvement was
a scintillation counter. The first screening achieved by introduction of a second p-flu-
hit 1 displayed a potency of IC50 = 15 000 oro-phenyl-substituent instead of an iso-
nM. During the early phase of the project a propyl group leading to compound 2. The