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References and notes
Table 4
In vitro profiling of conivaptan and 13d
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hV1a Binding Kia (nM)
hV2 Binding Kia (nM)
V1a/V2 Binding ratio Ki
0.43
0.36
1.19
3
11
0.27
21
0.79
15
0.05
41
838
0.05
<1
hV1a FLIPR Ca2+ IC50 (nM)
b
c
hV2 cAMP IC50 (nM)
V1a/V2 Functional ratio IC50
d
RLM t1/2 (min)
d
HLM t1/2 (min)
10
3
14. Maryanoff, B. E. Acc. Chem. Res. 2006, 39, 831.
Solubility (
l
g/mL)
<1
<1
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Cyp450 3A4, 2D6, 2C9e (%)
75, 17, 35
498.58
5
0, 0, 24
419.59
6
MW
cLog P
tPSA
78
29
Inhibition of [3H]-Arg-vasopressin binding to recombinant human vasopressin
V1a or V2 receptors (N = 2).
Functional measurement of intracellular calcium of hV1a receptor using FLIPR
dose–response.
Functional measurement of intracellular cAMP of hV2 receptor using lumines-
cence dose–response.
a
b
c
d
Profile screening concentration of 1
Profile screening concentration of 3
l
l
M in DMSO.
M in DMSO.
e
an improved Cyp450 profile over conivaptan. However, 13d was
identified as having metabolic liabilities, which would need to be
addressed with further optimization. Compound 13d had in-
creased clog P relative to conivaptan, however this could possibly
be improved by incorporating polar moieties, thereby increasing
its tPSA and aqueous solubility.
In summary, we have reported several biaryl amides containing
a chiral bicyclic amine that possess dual V1a/V2 vasopressin recep-
tor affinity. Many analogues, including 8g, 12g, 13d, and 13g, were
shown to have excellent V1a- (Ki 65.4 nM) and good V2-receptor (Ki
6104 nM) binding affinity. Compound 13d has undergone further
pharmacological and pharmaceutical evaluation and displayed
good V1a and moderate V2 functional activity with an improved
Cyp450 profile when compared to conivaptan. However, additional
optimization of 13d will be necessary to address its cellular func-
tional activity, metabolic liability, and limited aqueous solubility.
25. Trybulski, E. J. Annu. Rep. Med. Chem. 2001, 36, 159.
26. Venkatesan, A. M.; Grosu, G. T.; Failli, A. A.; Chan, P. S.; Coupet, J.; Saunders, T.;
Mazandarani, H.; Ru, X. Bioorg. Med. Chem. Lett. 2005, 15, 5003.
27. Compounds with similar structural motifs had been described for modulating
the activity of 11 b-hydroxysteroid dehydrogenase type 1 (11bHSDP1); see
Andersen, H. S.; Kampen, G. C. T.; Christensen, I. T.; Mogensen, J. P.; Larsen, A.
R.; Kilburn, J. P. WO Patent 2004089470, 2004.
28. Inhibition of [3H]-Arg-vasopressin binding to recombinant human vasopressin
V1a or V2 receptors (N = 2).
29. Purifications by chiral SFC (CO2/EtOH or MeOH eluent on ChiralPak AS-H,
ChiralPak AD-H or Pirkle Covalent (R,R) Whelk-01 columns).
30. The VCD spectra were measured using
a commercially available VCD
instrument ChiralIRTM (BioTools, Inc., Wauconda, IL). Each of the two
enantiomers was dissolved in DMSO-d6 (84 mM) and placed in a BaF2 cell
with a path length of 0.1 mm. The VCD spectrum of each sample and solvent
Acknowledgments
was measured for 8 h with
a
4 cmÀ1 resolution and the photo elastic
We thank Drs. Magid Abou-Gharbia, Tarek Mansour, and Albert
Robichaud for their support, the Discovery Analytical Chemistry
group for analytical and spectral determinations, and the Pharma-
ceutical Profiling groups for providing profiling data.
modulators optimized at 1400 cmÀ1
.
The VCD baseline was obtained by
subtracting the VCD of one enantiomer from that of the other then dividing by
two. The IR baseline was obtained by subtracting the IR spectrum of DMSO-d6
from that of the sample.