M. A. Xiang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2987–2989
2989
Biochem. Soc. Trans. 1979, 7, 861; (c) Jard, S. Kidney Int.,
Supp. 1988, 26, 38; (d) Thibonnier, M. Regul. Pep. 1992,
38, 1.
sulfone moiety (8j) resulted in an inactive compound in
both V1a and V2 binding assays. The 2-amino substi-
tuted compound 8k was also a V1a selective compound
with an IC50 of 10 nM and negligible potency in the V2
binding assay. Introduction of halogens on the phenyl
ring in the form of 2-fluoro (8l) and 2-chloro (8m)
substituted phenyl compounds, resulted in potent V1a
antagonists with moderate (180–550 nM) V2 antagonist
activity. The introduction of the dihalo substituted
phenyl ring compounds such as 2,6-dichloro (8n) and
2,4-dichloro (8o) did not alter the V1a/V2 potency profile
with respect to that observed for the monohalo substi-
tuted compounds (8l and 8m). Compound 8p bearing a
2-methyl,5-fluoro substituent provided a potent V1a and
V2 dual antagonist with IC50 values of 8 and 67 nM,
respectively. The introduction of a 2-phenyl group
resulted in compound 8q, bearing an excellent V1a and
V2 dual antagonist activity profile with IC50 values of 26
and 29 nM, respectively. Next, we sought to examine the
metabolic stability and solubility profiles of the com-
pounds of interest. We were disappointed to discover
that the metabolic profiles for the potent compounds of
this series were rather poor with half-lives in the human
microsomal stability assay consistently being less than
10 min. Solubilities of compounds of interest were
determined to be below detectable levels at both pH 2
and 7.4.
2. (a) Laszlo, F. A.; Laszlo, F., Jr.; De Wied, D. Pharmacol.
Rev. 1991, 43, 73; (b) Mah, S. C.; Hofbauer, K. G. Drugs
Fut. 1987, 12, 1055; (c) Paranjape, S. B.; Thibonnier, M.
Exp. Opin. Invest. Drugs 2001, 10, 825; (d) Trybulski, E. J.
In Annual Reports in Medicinal Chemistry; Doherty, A. H.,
Ed.; Academic: San Diego, 2001; Vol. 36, pp 159–168; (e)
Albright, J. D.; Chan, P. S. Curr. Pharm. Des. 1997, 3, 615;
(f) Matthews, J. W.; Hoekstra, W. J.; Andrade-Gordon, P.;
de Garavilla, L.; Demarest, K. T.; Erickson, E.; Greco, M.
N.; Gunnet, J. W.; Hageman, W.; Hecker, L. R.; Moore, J.
B.; Maryanoff, B. E. Bioorg. Med. Chem. Lett. 2003, 13,
753.
3. Lixivaptan: (a) Martinez-Castelao, A. Curr. Opin. Investig.
Drugs 2001, 2, 525; (b) Albright, J. D.; Reich, M. F.; Delos
Santos, E. G.; 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; (c) Albright, J. D.;
Delos Santos, E. G.; Dusza, J. P.; Chan, P. S.; Coupet, J.;
Ru, X.; Mazandarani, H. Bioorg. Med. Chem. Lett. 2000,
10, 695; Conivaptan: (a) Norman, P.; Leeson, P. A.;
Rabasseda, X.; Castaner, J.; Castaner, R. M. Drugs Fut.
2000, 25, 1121; (b) Matsushita, A.; Taniguchi, N.; Koshio,
H.; Yatsu, T.; Tanaka, A. Chem. Pharm. Bull. 2000, 48, 21;
Mozavaptan: (a) Prous, J.; Mealy, N.; Castaner, J. Drugs
Fut. 1993, 18, 802; (b) Ogawa, H.; Yamashita, H.; Kondo,
K.; Yamamura, Y.; Miyamoto, H.; Kan, K.; Kitano, K.;
Tanaka, M.; Nakaya, K.; Nakamura, S.; Mori, T.;
Tominaga, M.; Yabuuchi, Y. J. Med. Chem. 1996, 39,
3547.
4. Beavers, M. P.; Gunnet, J. W.; Hageman, W.; Miller, W.;
Moore, J. B.; Zhou, L.; Xiang, A.; Urbanski, M.; Combs,
D. W.; Mayo, K. H.; Demarest, K. T. Drug Des. Discov.
2001, 17, 243.
5. Mandai, T.; Ueda, M.; Hasegawa, S.; Kawada, M.; Tsuji,
J.; Saito, S. Tetrahedron Lett. 1990, 31, 4041.
6. All compounds provided satisfactory spectral data (1H
NMR, CI-MS/ESI/MS, and were homogeneous by TLC).
7. Rigas, A.; Levine, L. J. Pharmacol. Exp. Ther. 1984, 231,
230, Binding affinities were determined by measuring the
inhibition of 3[H] AVP binding to cloned human V1a and V2
receptors. Initial compounds prepared in this series were
subjected to the following functional assays and were
determined to be vasopressin antagonists: The accumula-
tion of cAMP was measured in transfected HEK-293 cells
expressing human V2 receptors and the intracellular
calcium mobilization was measured in HEK-293 cells
transfected to express human V1a receptors.
In summary, although we were able to identify novel
compounds that were both selective V1a receptor
antagonists in compounds 8b, 8g, 8i, and 8k as well as
dual V1a/V2 receptor antagonists in compounds 8p and
8q, lack of metabolic stability and a poor solubility
profile precluded further development of this series of
compounds. The spiro substituent does not appear to
regulate selectivity in this template, and could be a
probable cause of the poor metabolic stability and sol-
ubility profiles. Additional alterations in the scaffold are
underway and will be reported in due course.
References and notes
1. (a) Laszlo, F. A.; Laszlo, F., Jr. Drug News Perspect. 1993,
6, 591; (b) Michel, R. H.; Kirk, C. J.; Billah, M. M.