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Table 2
Table 4
Human liver microsomal stability, Caco-2 permeability values of selected compounds
Effect of CCK1/CCK2 dual receptor antagonists on CCK8s-stimulated plasma amylase
and pentagastrin-stimulated gastric acid secretion in the rat
Compd
HLM %rem 15 mina
Papp A to Bb
Papp B to Ac
Compd
Inhibition of amylasea
Inhibition of acid secretion,
4b
4c
4d
4e
4f
4g
4i
4j
61
69
65
50
47
54
65
76
0.1
0.1
0.19
1.97
1.25
4.76
0.34
4.36
1.05
0.37
b
pED50 sd (ED50
)
0.04
0.04
0.05
0.03
0.1
4a
4c
4g
4i
45 10%
65 11%
67 7%
5.1 0.1 (7.9
ND
ND
ND
l
mol/kg)
À5 31%
4j
67 8%
5.8 0.1 (1.6
lmol/kg)
0.02
a
Inhibition of CCK8s-stimulated plasma amylase (10 nmol/kg s.c. dosed 60 min
following oral administration of 30 mol/kg test compounds). Data are expressed at
a
Percent remaining after 15 min in the presence of pooled human liver micro-
l
somes and NADPH.
percentage of reduction in the plasma amylase AUC of the concentration–time
curve over 6 h (plasma sample time points: 1, 2, 4, 6 h following administration of
CCK8s).
b
Apparent compound permeability (10À6 cm/s) from apical to basolateral side of
Caco-2 monolayer grown on transwell plates.
c
b
Apparent compound permeability (10À6 cm/s) from basolateral to apical side of
Inhibition of gastric acid secretion stimulated by intravenous infusion of pen-
Caco-2 monolayer grown on transwell plates.
tagastrin (100 nmol/kg/h) in the anesthetized Ghosh and Schild rat model.11 Test
compounds were administered by intravenous bolus administration and responses
measured as % decrease in the pH of the gastric lumen perfusate.
Table 3
Rat pharmacokineticsa
CCK8s-stimulated pancreatic amylase secretion (Table 4). In addi-
tion, compounds 4a and 4j also potently inhibited pentagastrin-
stimulated gastric acid secretion, with oral pED50 values of 5.1
b
c
Compd
T1/2 (h)
VSS (mL/kg)
105
Cld (mL/kg/min)
Fe (%)
4d
4e
4h
4i
1.3 0.1
1.5 0.1
6.4 0.6
7.0 0.7
6.2 0.4
9
3.1 0.2
4.1 0.7
3.1 1.1
2.0 0.1
2.6 0.1
11
4
3
(ED50 = 5.3 mg/kg, 7.9
1.6 mol/kg) for 4j.
In conclusion, we have shown for the first time that good
lmol/kg) for 4a, and 5.8 (ED50 = 1.0 mg/kg,
145 36
215 85
129 12
203 55
1
6
2
4
l
14
9
4j
21
CCK1R/CCK2R dual affinity can be imparted to certain formerly
CCK2R selective anthranilic amides. Subsequently, compounds
were designed with ꢀ10Â selectivity for CCK2R/CCK1R that mani-
fested in potent in vivo inhibition of gastric acid secretion along
with moderate inhibition of pancreatic amylase production. It is
hypothesized that the moderate antagonism of the CCK1 receptor
may providing significant benefit for GERD patients from improved
lower esophageal sphincter function and gastric prokinesis while
still allowing periodic gall bladder contraction.
a
b
c
Calculated from at least 3 animals at iv and po doses of 2
Elimination half-life from the iv dose.
Steady-state volume of distribution.
Clearance from the iv dose.
Fraction absorbed from the oral dose ((AUCpo/AUCiv) Â 100).
lmol/kg.
d
e
quinoxaline heterocycles was surprising and contrasts our earlier
findings in a related series that the quinoxaline ring system was
less prone to oxidative metabolism than was the [2,1,3]-benzothia-
diazole ring system.9 We attribute this difference to the presence
of a net negative charge in the present compounds and consequent
resistance to CYP-mediated oxidation. In addition, Caco-2 perme-
ability measurements (Papp) showed that all of the compounds
tested possessed limited apical (A) to basolateral (B) permeability,
while displaying pronounced efflux (B to A).
References and notes
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The pharmacokinetic parameters of selected compounds were
then evaluated in the rat (Table 3). Following oral administration
of solutions 4d, 4e, 4h, 4i, and 4j showed low to moderate absorp-
tion (%F = 4–28), in line with results from the Caco-2 assay. Plasma
half-life values were high for analogs containing the anthranilic
R3 = I or R3 = Cl2 core (4h–j, T1/2 = 6.2–7.0 h). As predicted by liver
microsome studies, benzothiadiazole analog 4d showed an elimi-
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olinone congener 4e. Plasma clearance values were also observed
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