Chemistry Reference
In-Depth Information
the position of the ring heteroatoms were systematically varied (W, X, Y, and
Z; Figure 13.6), while the position of the tert-butylphenyl and the benzodioxane
groups remained constant. As a second phase of this study, we modified the
nature of the ''linker'' group (V; Figure 13.6) between the pyrimidine hetero-
cyclic core and the benzodioxane moiety to give compounds 22-25.
In this study of conformationally constrained analogues of the s-cis
conformer of cinnamide 6 we found that cyclization via ''Route A'' was det-
rimental to TRPV1 activity, while the 4-aminopyrimidine core was found to
be a suitable isosteric replacement for the acrylamide moiety [compound
15; hTRPV1 (Cap) IC
50
¼
44 nM]. This conformational constraint allowed
for a favorable planar alignment of the key pharmacophoric elements found in
cinnamide 6 (e.g., the benzodioxane and tert-butylphenyl) and also estab-
lished that the nitrogen adjacent to the aminobenzodioxane group in
pyrimidine 15 (i.e.,W
¼
N) could serve as a replacement for the cinnamide
carbonyl oxygen.
In the next phase of our investigation we made changes to the linking group
between the pyrimidine heterocycle and the benzodioxane moiety. We deter-
mined that the NH linker was not required for activity in this new series of
antagonists and found that it could be replaced with an oxygen atom and still
maintain potency (e.g., compound 24). Finally, we demonstrated that potent,
orally available TRPV1 antagonists could be prepared by combining the 7-
substituted quinoline and the (trifluoromethyl)phenyl groups (found in our
initial cinnamide SAR investigation)
49
with the new 4-oxypyrimidine core. In
fact, the new 4-oxypyrimidine derivative 26 was equipotent to cinnamide 7, but
it also had significantly improved pharmacokinetic properties (e.g., lower
clearance: rat Cl
in vivo
¼
1.2 vs. 3.9 L h
1
kg
1
, and higher oral bioavailability:
F
oral
¼
31% vs. 5%, respectively) (Figure 13.7).
Compound 26 was shown to be effective in vivo at blocking capsaicin-induced
hypothermia in rats; it did not, however, show significant activity in the CFA-
induced pain model.
54
We postulated that the minimal effect observed in the
pain model may be due to a combination of insucient intrinsic TRPV1
potency and inadequate exposure in vivo. Therefore, at this stage of our SAR
investigation we sought to improve not only the potency of the 4-oxypyrimidine
TRPV1 antagonists, but also to enhance their pharmacokinetic properties
in vivo.
56
CF
3
CF
3
Increased
Oral Bioavalability
N
N
N
O
Replaced
Acrylamide Core
N
N
O
7
26
hTRPV1(Cap) IC
50
= 4 nM
F
oral
= 31%
hTRPV1(Cap) IC
50
= 4 nM
F
oral
= 5%
Figure 13.7
Optimization of the central core leading to enhanced oral bioavailability.
Search WWH ::
Custom Search