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3611
in the form of the B-ring pyridine did not lead to an in-
crease in human P-gp susceptibility. Addition of the 50-
chloro on the C-ring provided compound 2m, but did
not greatly improve pharmacokinetics in the rat as was
noted for the B-ring phenyl (compounds 1 ! 2f). The
related ethyl ester variants (2n–o) also showed good B1
receptor affinity and superior oral bioavailability
(>50%) in the rat. As exemplified by tetrazole 2p, hetero-
cyclic replacements for the ester were not tolerated in
combination with the B-ring pyridine, due to the unac-
ceptably high human P-gp efflux ratios.
pyridine (B/P = 0.8). It is interesting to note that many
of the compounds showing improved Occ90’s had some-
what weaker B1 affinity in the binding assay. We believe
the improved receptor occupancy of compounds bearing
the B-ring pyridine is likely attributed to subtle improve-
ment in physical properties rendered by the presence of
the nitrogen heteroatom (lower logP and protein
binding).
Preferred compounds were examined for additional
pharmacokinetic evaluation in dog and rhesus (Table 3).
While addition of the 50-Cl in compound 2f led to an
improvement in rat PK relative to 1 (Table 1), little ben-
efit was seen in dog and monkey. Replacing the ester
with a tetrazole provided the compound (2j) which
had the best profile with half-lives in the dog and rhesus
of 13 and 4.2 hours, respectively. While compound 2m,
the B-ring pyridine version of compound 2f, showed
minimal improvement in rhesus, a significant increase
in bioavailability (66%) and half-life (6.6 h) was
observed in dog. The closely related analog 2n, which
lacks the 50-Cl group and has an ethyl ester in place of
methyl ester, had very similar PK properties in these
species compared to 1.
To further evaluate modifications made to the biphenyl
region of 1, select compounds were evaluated in the
ex vivo transgenic receptor mouse occupancy model.17
In addition, CNS penetration studies in African green
monkey (AGM) were implemented.18 Results are shown
in Table 2.
Addition of the 50-chloro group to the C-ring (2f) exhib-
ited improvement in both receptor occupancy efficiency
(Occ90 = 450 nM) and increased CNS brain to plasma
ratio in the AGM compared to 1. The closely related tet-
razole 2j did not result in any improvement in occu-
pancy or CNS levels over the ester. The most
important result obtained was the boost in receptor
occupancy efficiency afforded by the compounds con-
taining the B-ring pyridine. For example, pyridine 2l
had an Occ90 of 350 nM (vs 520 nM for 1) without less-
ening the CNS levels in the AGM. Gratifyingly, the
inclusion of the 50-chloro group on the C-ring of 2l pro-
In conclusion, a series of cyclopropanecarboxamide
containing compounds, bearing modifications to the
biphenyl sector, was prepared and evaluated as bradyki-
nin B1 receptor antagonists. Incorporation of a pyridine
in the proximal phenyl ring led to enhanced receptor
occupancy, while addition of a chlorine at the 50-posi-
tion of the distal phenyl ring led to improvements in
terms of pharmacokinetics and greater CNS penetra-
tion. These enhancements are best exemplified by com-
pounds 2l–n which represent a significant advance over
lead compound 1.
vided 2m which exhibited the best occupancy (Occ90
=
210 nM) in the series, as well as the highest brain to plas-
ma ratio in the AGM for compounds bearing the B-ring
Table 2. Receptor occupancy and monkey CNS penetration for
selected compounds
Acknowledgment
Compound Occ90 (nM) AGM brain/plasmab PBc logP
a
We are grateful to the analytical department for logP
and protein binding measurements.
1
520
450
540
350
210
225
0.4
1.1
0.3
0.5
0.8
0.7
98.6 >3.6
97.4 >3.8
99.1 >3.8
2f
2j
2l
97.2
97.5
98.4
3.2
3.3
3.6
2m
2n
References and notes
a Values are means of at least eight experiments.
b Values are a mean of two experiments.
c Protein binding measured using 10% rat serum.
1. Couture, R.; Harrisson, M.; Vianna, R. M.; Cloutier, F.
Eur. J. Pharmacol. 2001, 429, 161.
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2. Regoli, D.; Barabe, J. Pharmacol. Rev. 1980, 32, 1.
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5. Mason, G. S.; Cumberbatch, M. J.; Hill, R. G.; Rupniak,
N. M. J. Can. J. Physiol. Pharmacol. 2002, 80, 264.
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Table 3. Dog and Rhesus Pharmacokinetics for select compounds
Compound
Dog PKa
Rhesus PKb
F (%) t1/2 (h) Cl
F (%) t1/2 (h) Cl
1
33
19
87
66
20
1.8
1.6
9.0 31
1.7
3.9
4.2
2.5
1.1
13
2f
2j
20
20
1.2 75
6.2 12
11.2
3.4
13
2m
2n
6.6
2.3
16.9
11.5
10
12
a Mongrel dogs (n = 2). Oral dose 3 mg/kg, iv dose = 1 mg/kg. Inter-
animal variability was less than 20% for all values.
b Rhesus monkeys (n = 2). Oral dose 3 mg/kg, iv dose = 1 mg/kg.
Interanimal variability was less than 20% for all values.