M. A. Xiang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6623–6628
Table 2. Effect of 3 on urine volume and osmolality in ratsa
6627
2. (a) Matthews, J. M.; Greco, M. N.; Hecker, L. R.;
Hoekstra, W. J.; Andrade-Gordon, P.; de Garavilla, L.;
Demarest, K. T.; Ericson, E.; Gunnet, J. W.; Hageman,
W.; Look, R.; Moore, J. B.; Maryanoff, B. E. Bioorg. Med.
Chem. Lett. 2003, 13, 753; (b) Dyatkin, A. B.; Hoekstra,
W. J.; Hlasta, D. J.; Andrade-Gordon, P.; de Garavilla,
L.; Demarest, K. T.; Gunnet, J. W.; Hageman, W.; Look,
R.; Maryanoff, B. E. Bioorg. Med. Chem. Lett. 2002, 12,
3081; (c) Matthews, J. M.; Hoekstra, W. J.; Dyatkin, A.
B.; Hecker, L. R.; Hlasta, D. J.; Poulter, B. L.; Andrade-
Gordon, P.; de Garavilla, L.; Demarest, K. T.; Ericson,
E.; Gunnet, J. W.; Hageman, W.; Look, R.; Moore, J. B.;
Reynolds, C. H.; Maryanoff, B. E. Bioorg. Med. Chem.
Lett. 2004, 14, 2747; (d) Matthews, J. M.; Hlasta, D. J.;
Andrade-Gordon, P.; Demarest, K. T.; Ericson, E.;
Gunnet, J. W.; Hageman, W.; Look, R.; Moore, J. B.;
Maryanoff, B. E. Lett. Drug Des. Discov. 2005, 2, 601; (e)
Hoekstra, W. J.; Dyatkin, A. B.; Maryanoff, B. E.;
Matthews, J. M. U.S. Patent 6,713,475, 2004; (f) Urban-
ski, M. J.; Chen, R. H.; Demarest, K. T.; Gunnet, J.;
Look, R.; Ericson, E.; Murray, W. V.; Rybczynski, P. J.;
Zhang, X. Bioorg. Med. Chem. Lett. 2003, 13, 4031.
3. (a) Gunnet, J. W.; Matthews, J. M.; Maryanoff, B. E.; de
Garavilla, L.; Andrade-Gordon, P.; Damiano, B.; Hag-
eman, W.; Look, R.; Stahle, P.; Streeter, A.; Wines, P. G.;
Demarest, K. T. Clin. Exp. Pharmacol. Physiol. 2006, 33,
320; (b) Ros, J.; Fernandez-Varo, G.; Munoz-Luque, J.;
Arroyo, V.; Rodes, J.; Gunnet, J. W.; Demarest, K. T.;
Jimenez, W. Br. J. Pharmacol. 2005, 146, 654.
4. (a) Xiang, M. A.; Chen, R. H.; Demarest, K. T.; Gunnet,
J.; Look, R.; Hageman, W.; Murray, W. V.; Combs, D.
W.; Patel, M. Bioorg. Med. Chem. Lett. 2004, 14, 2987; (b)
Xiang, M. A.; Chen, R. H.; Demarest, K. T.; Gunnet, J.;
Look, R.; Hageman, W.; Murray, W. V.; Combs, D. W.;
Rybczynski, P. J.; Patel, M. Bioorg. Med. Chem. Lett.
2004, 14, 3143; (c) Patel, M.; Rybczynski, P. J.; Xiang, M.
A. U.S. Pat. Appl., US2004266752, 2004; (d) Chen, R. H.;
Xiang, M. A. PCT Int. Appl., WO2002002531, 2002.
5. (a) Francis, G. S.; Tang, W. H. W. JAMA 2004, 291, 2017;
(b) Goldsmith, S. R.; Gheorghiade, M. J. Am. Coll.
Cardiol. 2005, 46, 1785.
Dose, p.o.
(mg/kg)
Urine
volume
(mL)
Urine
Urine
Urine
volume
% vehicle
osmolality
(mOsm/kg)
osmolality
% vehicle
Vehicle
2.3 0.4
3.0 0.2
3.8 0.5b
7.2 1.5b
15.9 2.5b
1070 150
920 89
510 110b
560 110b
180 26b
1
3
130
165
310
690
87
48
52
17
10
30
a Compound 3 was administered orally to conscious hydrated male rats
at the specified dose level. Each value represents the mean SE
(N = 6–10).
b P < 0.05 versus the vehicle values (Dunnett’s multiple comparison
test).
690% increase of urine output over untreated controls,
with an 83% reduction of urine osmolality. By way of
comparison, a 10 mg/kg oral dose of lixivaptan (VPA-
985) is reported to alter urine output/osmolality by
+450%/ꢃ70%.7a Compound 3 was also an efficacious
aquaretic agent in female beagle dogs (at 30 mg/kg,
p.o., urine output and osmolality were altered by
+1130% and ꢃ78%) and cynomolgus monkeys.13
To assess the V1a activity of 3 in vivo, we evaluated its
ability to reverse hypertension in rats induced by Arg-
vasopressin. We infused a saline solution of Arg-vaso-
pressin intravenously (30 ng/kg/min) to male Long–
Evans rats to produce a stable increase in mean arterial
pressure of 40–60 mm Hg. The test compound was
administered i.v. in cumulative doses and the reduction
in blood pressure was monitored. The ED50 for 3 (from
a linear section of the dose–response curve) was
644 123 lg/kg (N = 6).14
In conclusion, we manipulated the structure of dual
vasopressin V1a/V2 receptor antagonist 2 to devise a
suitable backup compound for clinical development.
The amide group was changed to a carboxylic acid;
the pendant phenyl group was changed to a chloro;
and fluoro and methoxy substituents were added. The
resultant analogue, 3, is a potent, dual V1a/V2 antagonist
with functional activity in vitro and in vivo. In addition,
3 possesses favorable attributes for advancement as a
clinical candidate.15 Consequently, 3 (RWJ-676070;
JNJ-17158063)1a,4c is now undergoing clinical studies
in humans.16
6. (a) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney,
P. J. Adv. Drug Delivery Rev. 1997, 23, 3; (b) Veber, D. F.;
Johnson, S. R.; Cheng, H.-Y.; Smith, B. R.; Ward, K. W.;
Kopple, K. D. J. Med. Chem. 2002, 45, 2615.
7. (a) Albright, J. D.; Reich, M. F.; Santos, E. G. D.; Dusza,
J. P.; Sum, F. W.; Venkatesan, A. M.; Coupet, J.; Chan, P.
S.; Ru, X.; Mazandarani, H.; Bailey, T. J. Med. Chem.
1998, 41, 2442; (b) Matsuhisa, A.; Taniguchi, N.; Koshio,
H.; Yatsu, T.; Tanaka, A. Chem. Pharm. Bull. 2000, 48, 21.
8. (a) Zhong, H. M. et al., Unpublished results; presented at
the 228th ACS National Meeting, Philadelphia, PA, Aug
22–26, 2004, ORGN-524; (b) See: Deng, X.; Kenny, B.;
Liang, J. T.; Mani, N.; Villani, F. J.; Zhang-Plasket, F.;
Zhong, H. U.S. Pat. Appl., US2004259857, 2004.
Acknowledgments
9. Single crystals of [(R)-C15H18NO2][(1R)-(ꢃ)-C10H15SO4]
(from MeOH, mp 289–291 °C) are orthorhombic [space
group P212121–D2 (No. 19)] with a = 7.095(3) A,
We thank Michael J. Costanzo for helpful discussions
and advice. We thank Victor Day of the Crystalytics
Company for the single-crystal X-ray diffraction study
on intermediate I.
4
˚
3
b = 15.592(5) A, c = 21.478(7) A, V = 2376(1) A , and
˚
˚
˚
Z = 4 cation/anion formula units [dcalcd = 1.330 g cmꢃ3
;
la(MoKa) = 0.178 mmꢃ1]. A total of 3285 reflections
having 2h (Mo Ka) < 50.7° were collected on a Bruker
P4 diffractometer using 1.20°-wide x scans and graphite-
˚
monochromated Mo Ka radiation (k = 0.71073 A); 3081
References and notes
of these reflections were unique. Lattice constants were
determined with the Bruker XSCANS software package
using 35 centered reflections. ‘Direct methods’ were used
to solve the structure and the resulting structural param-
eters were refined with F2 data to convergence by using
1. (a) Maryanoff, B. E. Acc. Chem. Res. 2006, 39, 831; (b)
Maryanoff, B. E. In Drug Discovery and Development;
Chorghade, M. S., Ed.; Wiley: Hoboken, NJ, 2006; Vol. 1,
pp. 313–337.