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C. A. Blum et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4573–4577
Table 5
Rat pharmacokinetics for selected aminoquinazolinesa
Compound
iv dose (mg/kg)
2.7
Cl (mL/min/kg)
23
Vss (L/kg)
T1/2 (h)
po dose (mg/kg)
AUC0–in (ng h/mL)
Tmax (h)
Cmax (ng/mL)
f (%)
2
13
8
2.0
121
1426
7617
1449
982
3.0
0.67
5.7
1.7
1.8
0.9
3.7
13
101
137
211
137
93
8
99
89
94
61
—
2.0b
2.0
44
48
1.5
1.5
4.2
22
12
5.5
38
4.2
2.0b
2.1c
2.0
55
18
—
1.0
—
5.3
—
3.5
—
6.9
218
3251
2.0
215
50
a
Dosed in 50% PEG-400/water (iv) and 0.5% methylcellulose, 0.1% triacetin (po) unless otherwise indicated.
Vehicle was 2% vitamin E TPGS/water.
Dosed as the HCl salt.
b
c
44 degrades by ꢀ70% after 6 h and ꢀ57% after 4 h (approximate
stomach transit time in humans). The hydrolysis products were
identified as the parent quinazolin-4-one and the 2-amino-5-triflu-
romethyl-pyridine. By comparison, 48 degraded by only 3% and 18
by only 1%, both over 6 h. Adequate exposure was achieved with 48
when dosed in vitamin E-TPGS (Table 5) or in MC as the HCl salt
(AUC 982 ng h/mL @ 2.1 mg/kg). The potent amino-methyl analog
55 was stable in rat microsomal preparations13 but was poorly ab-
sorbed following oral dosing in methylcellulose (Table 5). The 2-
methoxymethyl analog (18) exhibited the best overall pharmaco-
kinetic profile in rat with low clearance (5.3 mL/min/kg), moderate
volume of distribution (3.5 L/kg), and a half-life of about 7 h. In
addition, 18 is 4- to 5-fold more potent than 48 in vitro (1.5 nM
vs 7.0 nM). Quinazoline 18 fully inhibited carrageenan-induced
thermal hyperalgesia (CITH) in rats following a 3 mg/kg oral dose
and led to a significant reversal of thermal hyperalgesia at doses
as low as 0.3 mg/kg (Fig. 2). Although it proved to be particularly
difficult to increase aqueous solubility starting from our lead
aminoquinazoline (2), the excellent cellular permeability of 18
may be one of the factors contributing to the excellent in vivo per-
formance of this compound. Experiments in MDCK-MDR1 cells
suggest that p-glycoprotein-mediated efflux mechanisms are not
an issue with this compound (Table 6). These data are important
in light of evidence that central exposure may be an important
parameter for achieving broad spectrum analgesic effects with
TRPV1 antagonists in preclinical pain models.15 Consistent with
the robust effect observed in CITH, 18 demonstrated significant
brain penetration with a brain-to-plasma ratio of ꢀ1.8 (Table 6).
In summary, initial SAR exploration of lead aminoquinazoline
(2) at C-2 has led to a number of potent TRPV1 antagonists with
improved pharmacokinetic properties. In addition, we have further
Table 6
Key in vitro and in vivo data for 18
hTRPV1-cap
(nM)a
rTRPV1-pH
(nM)b
MDCK PApp
hERG
(%In @ 3
CITH MED
b/pf
1.8
(Â10À6 cm)c
l
M)d
(mg/kg)e
1.5
0.5
A ? B 14 ( 5)
B ? A 17 ( 2)
44
0.3
a
IC50 at human TRPV1 receptor activated by capsaicin.
IC50 at rat TRPV1 receptor activated by low pH.
Permeability in MDCK cells over-expressing Pgp.
See Table 4.
b
c
d
e
Minimum effective oral dose to reverse carrageenan-induced thermal hyper-
algesia (CITH).
f
Brain-to-plasma ratio at 4 h following a 3 mg/kg oral dose in rats (vit E-TPGS
vehicle).
demonstrated the utility of this series with respect to efficacy in an
acute inflammatory pain model in rats. The 2-methoxymethyl
analog 18 exhibits good in vitro and in vivo potency (CITH) and
is well absorbed following oral dosing. Unfortunately, hERG data
suggest that cardiac QT interval prolongation may be a potential
risk with this compound (Table 5). To address this potential liabil-
ity, further optimization of this series will be the topic of future
communications.
Acknowledgments
The authors gratefully acknowledge the electrophysiology work
of John Dessaint and Gina Borrelli. The authors also thank Lauren
Danner (cell culture) and Du-Shieng Chien (pharmacokinetics).
References and notes
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Figure 2. Effect of 18 (0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg) and ibuprofen (10 mg/kg)
on carrageenan-induced thermal hyperalgesia following oral dosing in rats.
*p < 0.05 (see Ref. 14).
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