Chemistry Reference
In-Depth Information
potency in the acid-mediated assay could be obtained by substituting the 2-
position of the quinoline ring with an amino group [compound 27; hTRPV1
(pH 5), IC
50
¼
73 nM]. However, metabolite identification studies in rat hepa-
tocytes showed that compound 27 was still extensively metabolized on the 2-
aminoquinoline moiety (Figure 13.8).
With this information in hand, we prepared a series of analogs designed
to block the proposed sites of metabolism, focusing on the 2-aminopyridyl
portion of 27. The 2-aminobenzothiazole analogue 28 was designed to block
two of the proposed metabolic hot spots on the quinoline ring of 27
by replacing the C3-C4 atoms with sulfur. This modification resulted in a
dramatic improvement in the metabolic stability in human liver micosomes
(Cl
in vitro
o
5 mLmin
1
mg
1
). In addition, compound 28 showed a 6-fold
improvement in potency over 27 in the capsaicin-mediated assay (IC
50
¼
1.2
nM vs. 7 nM); however, activity in the acid-mediated assay was sacrificed
(IC
50
44000 nM).
It had been our experience that subtle modifications to this region of
the heterocycle can impact activity in the TRPV1 acid-mediated assay.
Therefore, a series of compounds was prepared to investigate the effect of an
additional substitution on the nitrogen of compound 28. We found that the
N-acylated analogue 29 had enhanced potency in both assays (IC
50
¼
0.76
and 0.62 nM in the capsaicin- and acid-mediated assays, respectively), while
also maintaining excellent metabolic stability in human liver micosomes
(Cl
in vitro
o
5 mLmin
1
mg
1
).
With compound 29 selected as the lead candidate, its pharmacokinetic
properties were examined in rats, dogs, and monkeys (Table 13.1). In all species
examined, compound 29 exhibited low clearance and moderately high volumes
of distribution, with consequently long half-lives. Oral bioavailability among
the three species tested ranged from 23 to 52%.
Table 13.1 Mean pharmacokinetic parameters for compound 29 following i.v.
and p.o. administration to fasted rat, dog, and monkey, with
projected values for human.
Oral
dosing
b
Intravenous dosing
a
AUC
0
inf
(ng h mL
1
)
Cl
(mL h
1
kg
1
)
V
ss
(mL kg
1
)t
1/2
(h)
Species
F (%)
Rat 8800 120 4000 31 51
Dog 7400 140 7000 41 23
Monkey 37000 30 2300 62 52
Human (projected) - 50 4500 60-120 -
a
1mgkg
1
in 80% PEG-400/H
2
O; n
¼
3 animals per group. Variability for AUC
0-inf
,Cl, V
ss
, and
t
1/2
values ranged from 7 to 38% for all species.
b
1mgkg
1
suspension in 10% Pluronic/Oraplus; n
¼
3 animals per group. Variability for F
oral
ranged from 26 to 50% for all species.
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