J. Bao et al. / Bioorg. Med. Chem. Lett. 20 (2010) 2354–2358
2357
Table 2
Table 4
Activities of compounds with b non-aromatic substituents
Pharmacokinetic profile of 40
CF3
t1/2 (h) Vd (L/kg) Clp (mL/mg/kg) nAUC (po) (
l
M h kg/mg) F (%)
5.3
44
Rat 2.8
Dog 8.8
7.2
11
33
17
0.05
0.69
CF3
O
O
N
Table 5
P450 inhibition and hPXR induction data for compound 40
R
F
IP-1b
%
Gerbil FTc
Cyp 2C9
36.5
Cyp 2D6
35.7
Cyp 3A4
>50
PXR
>30
Compd
R
NK1
+50 %HS
a
IC50 (lM)
IC50 (nM)
% Inhibition
O
O
fast
34
35
0.066
1.4
2.4
5
5
98d
96d
O isomer
At 1 h, the IC50 values in plasma and brain are 0.57 and 6.9 nM,
respectively indicating that low plasma and brain concentrations
drive efficacy in gerbil and a high b/p ratio.
slow
isomer
0.11
O
Compound 40 was evaluated for PK properties in rat and dog
(Table 4). In rat, it showed high clearance (33 mL/min/kg), very
low oral AUC (0.05), desirable plasma half-life (2.8 h) and poor oral
bioavailability. However, in dog, the PK profile improved with
moderate clearance (11 mL/min/kg), better oral AUC (0.69), good
half-life, and improved oral bioavailability.
Compound 40 had a low affinity for cytochrome P450 enzymes
and a reduced potential for induction as measured by a hPXR
induction assay (Table 5), which indicated that compound 40
may have reduced liability for drug–drug interactions.
N
OH
OH
36
37
38
39
40
41
0.16
0.18
0.18
0.09
0.18
0.041
11
4
82
13
8
—
O
9.6
3.2
1.9
0.21
14
3
—
100d
100
91
O
N
N
2
4
In summary, a new class of NK1 receptor antagonists based on a
tetrahydroindolizinone core with substitutions at the 7-position
has been identified. These 6,5-fused pyrrolidine NK1 antagonists
generally had sub-nanomolar NK1 binding affinities and excellent
functional IP-1 activities. Many of these analogs have potent
in vivo efficacy in the gerbil model at 24 h. Compound 40 had
excellent efficacy in the gerbil foot tapping model at both 1 h
and 24 h. It also had a clean profile in human P450 inhibition and
PXR induction assays, thus reducing the potential for drug–drug
interactions.
a
Displacement of [125I] labelled substance P from the cloned hNK1 receptor
expressed in CHO cells. Data are mean (n = 3).8
b
IP-1 assay9: Measure the response of inositol phosphate generation to sub-
stance P (10 lM) and reported as the percent of substance P response remaining
(SPRR) at 100 nM NK1 antagonist concentration x.
c
Inhibition of GR73632 induced foot tapping in gerbils@ 3 mg/kg iv at 24 h.10
1 h at 1 mg/kg.
d
group at the far side of the attachment to reduce serum shifts. All
of them exhibited sub-nanomolar binding potency on the NK1
receptor. They had lower shifts in affinity in the presence of human
serum as compared to the compounds with b-aromatic substitu-
ents, probably due to higher polarity. Importantly, all of them
had excellent functional activities. In the gerbil foot tapping assay,
all tested compounds displayed potent efficacy at 1 h or 24 h. Com-
pound 40 was prepared initially as an intermediate for compound
41. The t-Bu group of compound 41 was used to block possible
metabolism of the piperidine group. It was surprising to find that
compound 40 is more potent than 41 in the gerbil foot tapping as-
say despite the fact that compound 41 is about fourfold (ninefold
with human serum) more potent than compound 40 in the binding
assay.
Acknowledgments
The authors wish to thank the Synthetic Services Group for
scale-up of synthetic intermediate 2.
References and notes
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Pharmacol. Med. Chem. 1997, 326, 201.
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E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N. N.; Tattersall, F.
D.; Rupniak, N.; Williams, A.; Rycroft, W.; Hargreaves, R. J.; MacIntyre, D. E. J.
Med. Chem. 1998, 41, 4607.
Given its single dose potency in the gerbil foot tapping assay,
compound 40 was titrated to have an ID50 = 0.05 mg/kg at 1 h
and an ID50 = 0.49 mg/kg at 24 h (Table 3). These data indicate that
compound 40 was one of the most potent compounds in this assay.
6. Morriello, G. J.; Devita, R. J.; Mills, S. G.; Young, J. R.; Lin, P.; Doss, G.; Chicchi, G.
G.; DeMartino, J.; Kurtz, M.; Tsao, K. C.; Carlson, E.; Townson, K.; Wheeldon, A.;
Boyce, S.; Collinson, N.; Rupniak, N.; Moore, S. Bioorg. Med. Chem. 2008, 16,
2156.
7. (a) Morriello, G. J.; Mills, S. G.; Johnson, T.; Reibarkh, M.; Chicchi, G.; DeMartino,
J.; Kurtz, M.; Davies, P.; Tsao, K. C.; Carlson, E.; Townson, K.; Tattersall, F. D.;
Wheeldon, A.; Boyce, S.; Collinson, N.; Rupniak, N.; Moore, S.; Devita, R. J.
Bioorg. Med. Chem. Lett. 2010, 20, 2007; (b) For detailed procedures for
synthesis of the compounds in this Letter: Bao, J.; Devita, R. J.; Mills, S. G.;
Morriello, G. J. WO 2007136570.
Table 3
In vivo activity of compound 40 in Gerbila
Time (h)
ID50
ID50 (at 1 mpk, iv)
Plasma
Brain
1
24
0.05
0.49
0.57
—
6.9
—
8. NK1 binding assay: Cascieri, M. A.; Ber, E.; Fong, T. M.; Sadowski, S.; Bansal, A.;
Swain, C. J.; Seward, E. M.; Frances, B.; Burns, D.; Strader, C. D. Mol. Pharmacol.
1992, 42, 458.
a
Plasma drug levels determined by LC–MS following protein precipitation.