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G. J. Morriello et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5925–5932
Table 5
Lead compound of tricyclic hNK1 antagonists
O
CF3
H
N
O
HO
H
H
CF3
F
IC50: 0.06 nM
IC50 + 50% serum:
Human: 0.7 nM
Dog: 1.5 nM
Rhesus: 0.4 nM
Rat: 0.4 nM
Ancillary activity:
CYP inhibition
2D6: 17.38
3A4: 22.68
2C9: 43.12
hPXR: 3.77 lM (38%)
lM
lM
lM
Gerbil: 1.9 nM
*
IP-1: 2% SP remaining (36%SP at 1 nM dose)
GFT:
Gerbil PK/PD iv study:
IC50 = 2.2 nM (1 h brain)
IC50 = 4.3 nM (1 h plasma)
ID50 = 0.02 mg/kg (1 h)
ID50 = 0.02 mg/kg (24 h)
Microsomal stability % remaining (60 min)
Dog: 90%
Human: 96%
Rat: 96%
Rhesus: 99%
Pharmocokinetics
Rat
Dog
0.50
58.02
n/a
Clp (ml/min/kg)
t1/2: (h)
MRT: (h)
Vd: (L/Kg)
F%
3.24
14.60
4.67
4.03
88.83
n/a
BSA for 15 min. Antagonists (100 nM) or anhydrous DMSO were added for
30 min before substance P (up to 10 M) was added for another 30 min. The
reaction was terminated by removal of the medium and addition of formic acid.
The supernatant was aged for 60 min at 22 °C. Lysates (15 L) were incubated
m) SPA beads (Amersham) in
Acknowledgments
l
The authors thank George Doss for the NMR characterizations of
compounds 1, 9a,9b, 14a, 14b, 20, and Paul Finke for his assistance
in the preparation of this Letter.
l
with 1 mg RNA Binding Yittrium Silicate (2–5
l
Optiplates with shaking for 2 h. [H3]-inositol phosphate generation was
quantitated on a Packard Topcount and the data were analyzed using Prism
(GraphPad).
6. Young, J. R.; Eid, R.; Turner, C.; DeVita, R. J.; Kurtz, M. M.; Tsao, K.-L. C.; Chicchi,
G. G.; Wheeldon, A.; Carlson, E.; Mills, S. G. Bioorg. Med. Chem. Lett. 2007, 17,
5310.
7. (a) Devita, R.; Mills, S. G.; Jiang, J.; et al. World Patent 2006/060344, 2006.; (b)
Devita, R.; Mills, S. G.; Jiang, J.; et al. World Patent 2006/060346, 2006.
8. (a) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480; (b)
Mancuso, A. J.; Swern, D. Synthesis 1981, 3, 165.
Supplementary data
Supplementary data associated with this article can be found, in
9. (a) Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580, 44; (b) Wadsworth, W.
S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 7, 1733.
References and notes
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5. CHO cells (2.5 Â 104) expressing recombinant human NK1 receptors were
plated in 96-well tissue culture dishes and left overnight. This was then
followed by prelabeling overnight with [H3]-myo-inositol (10–25 Ci/mmol) in
inositol-free medium with 0.02% BSA at 37 °C. The cells were then incubated
with 10 mM LiCl in Hepes-buffered inositol-free (DMEM) medium with 0.02%