6002 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 16
Meyers et al.
antagonism to maximal angiotensin-converting enzyme inhibition in
diabetic nephropathy. J. Am. Soc. Nephrol. 2009, 20, 2641–2650. (b)
Williams, G. H.; Burgess, E.; Kolloch, R. E.; Ruilope, L. M.; Niegowska,
J.; Kipnes, M. S.; Roniker, B.; Patrick, J. L.; Krause, S. L. Efficacy of
eplerenone versus enalapril as monotherapy in systemic hypertension.
Clin. Exp. Pharmacol. Physiol. 2006, 33, 990–996.
Padwa, A., Ed.; Wiley: New York, 1984; Chapter 7. (c) Manyem, S.; Sibi,
ꢀ
M. P.; Lushington, G. H.; Neuenswander, B.; Schoenen, F.; Aube, J.
Solution-phase parallel synthesis of a library of Δ2-pyrazolines. J. Comb.
Chem. 2007, 9, 20–28.
(15) Foti, F.; Grassi, G.; Risitano, F. First synthesis of a bromonitri-
limine. Direct formation of 3-bromopyrazole derivatives. Tetra-
hedron Lett. 1999, 40, 2605–2606.
(7) De Gasparo, M.; Whitebread, S. E.; Preiswerk, G.; Jeunemaitre,
X.; Corvol, P.; Menard, J. Antialdosterones: incidence and pre-
vention of sexual side effects. J. Steroid Biochem. 1989, 32 (1B),
223–227.
(8) For a recent review, see the following: (a) Meyers, M. J.; Hu, X.
Non-steroidal mineralocorticoid receptor antagonists. Expert
Opin. Ther. Pat. 2007, 17, 17–23 and references therein . (b) Bell,
M. G.; Gernert, D. L.; Grese, T. A.; Belvo, M. D.; Borromeo, P. S.;
Kelley, S. A.; Kennedy, J. H.; Kolis, S. P.; Lander, P. A.; Richey, R.;
Sharp, V. S.; Stephenson, G. A.; Williams, J. D.; Yu, H.; Zimmerman,
K. M.; Steinberg, M. I.; Jadhav, P. K. (S)-N-{3-[1-Cyclopropyl-1-(2,4-
difluoro-phenyl)-ethyl]-1H-indol-7-yl}-methanesulfonamide: a potent,
nonsteroidal, functional antagonist of the mineralocorticoid receptor.
J. Med. Chem. 2007, 50, 6443–6445.
(16) Freudenberger, J. H.; Lahm, G. P.; Selby, T. P.; Stevenson, T. M.
Substituted Dihydro 3-Halo-1H-pyrazole-5-carboxylates Their
Preparation and Use. WO 03/016283, February 27, 2003.
(17) (a) Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. Medicinal
chemistry of hERG optimizations: highlights and hang-ups.
J. Med. Chem. 2006, 17, 5029–5046. (b) Jalaie, M.; Holsworth,
D. D. QT interval prolongation: and the beat goes on. Mini-Rev.
Med. Chem. 2005, 5, 1083–1091. (c) The dofetilide assay was
performed as previously reported: Singleton, D. H.; Boyd, H.; Steidl-
Nichols, J. V.; Deacon, M.; de Groot, M. J.; Price, D.; Nettleton, D. O.;
Wallace, N. K.; Troutman, M. D.; Williams, C.; Boyd, J. G. Fluores-
cently labeled analogues of dofetilide as high-affinity fluorescence
polarization ligands for the human ether-a-go-go-related gene (hERG)
channel. J. Med. Chem. 2007, 50, 2931–2941. (d) The hERG patch-
clamp assay was performed as previously reported: Volberg, W. A.;
Koci, B. J.; Su, W.; Lin, J.; Zho, J. Blockade of human cardiac
potassium channel human ether-a-go-go-related gene (HERG) by
macrolide antibiotics. J. Pharmacol. Exp. Ther. 2002, 302, 320–327.
(18) Li, Y.; Suino, K.; Daugherty, J.; Xu, H. E. Structural and bio-
chemical mechanisms for the specificity of hormone binding and
coactivator assembly by mineralocorticoid receptor. Mol. Cell
2005, 19, 367–380.
(19) (a) Sun, C.; Robl, J. A.; Wang, T. C.; Huang, Y.; Kuhns, J. E.;
Lupisella, J. A.; Beehler, B. C.; Golla, R.; Sleph, P. G.; Seethala, R.;
Fura, A.; Krystek, S. R., Jr.; An, Y.; Malley, M. F.; Sack, J. S.;
Salvati, M. E.; Grover, G. J.; Ostrowski, J. O.; Hamann, L. G.
Discovery of potent, orally-active, and muscle-selective androgen
receptor modulators based on an N-aryl-hydroxybicyclohydantoin
scaffold. J. Med. Chem. 2006, 49, 7596–7599. (b) Nirschl, A. A.; Zou,
Y.; Krystek, S. R.; Sutton, J. C.; Simpkins, L. M.; Lupisella, J. A.;
Kuhns, J. E.; Seethala, R.; Golla, R.; Sleph, P. G.; Beehler, B. C.;
Grover, G. J.; Egan, D.; Fura, A.; Vyas, V. P.; Li, Y. X.; Sack, J. S.; Kish,
K. F.; An, Y.; Bryson, J. A.; Gougoutas, J. Z.; DiMarco, J.; Zahler, R.;
Ostrowski, J.; Hamann, L. G. N-Aryl-oxazolidin-2-imine muscle se-
lective androgen receptor modulators enhance potency through phar-
macophore reorientation. J. Med. Chem. 2009, 52, 2794–2798. (c)
Bohl, C. E.; Wu, Z.; Chen, J.; Mohler, M. L.; Yang, J.; Hwang, D. J.;
Mustafa, S.; Miller, D. D.; Bell, C. E.; Dalton, J. T. Effect of B-ring
substitution pattern on binding mode of propionamide selective andro-
gen receptor modulators. Bioorg. Med. Chem. Lett. 2008, 18, 5567–
5570. (d) Ostrowski, J.; Kuhns, J. E.; Lupisella, J. A.; Manfredi, M. C.;
Beehler, B. C.; Krystek, S. R.; Bi, Y.; Sun, C.; Seethala, R.; Golla, R.;
Sleph, P. G.; Fura, A.; An, Y.; Kish, K. F.; Sack, J. S.; Mookhtiar, K. A.;
Grover, G. J.; Hamann, L. G. Pharmacological and X-ray structural
characterization of a novel selective androgen receptor modulator:
potent hyperanabolic stimulation of skeletal muscle with hypostimula-
tion of prostate in rats. Endocrinolgy 2007, 148, 4–12. (e) Bohl, C. E.;
Gao, W.; Miller, D. D.; Bell, C. E.; Dalton, J. T. Structural basis for
antagonism and resistance of bicalutamide in prostate cancer. Proc.
Natl. Acad. Sci. U.S.A. 2005, 102, 6201–6206. (f ) Zhang, Z.; Olland,
A. M.; Zhu, Y.; Cohen, J.; Berrodin, T.; Chippari, S.; Appavu, C.; Li, S.;
Wilhem, J.; Chopra, R.; Fensome, A.; Zhang, P.; Wrobel, J.; Unwalla,
R. J.; Lyttle, C. R.; Winneker, R. C. Molecular and pharmacological
properties of a potent and selective novel nonsteroidal progeste-
rone receptor agonist tanaproget. J. Biol. Chem. 2005, 280, 28468–
28475.
(9) (a) Dietz, J. D.; Du, S.; Bolten, C. W.; Payne, M. A.; Xia, C.; Blinn,
J. R.; Funder, J. W.; Hu, X. A number of marketed dihydropyr-
idine calcium channel blockers have mineralocorticoid receptor
antagonist activity. Hypertension 2008, 51, 42–748. (b) Fukumoto,
S.; Ohra, T.; Sakamoto, J. Aldosterone Receptor Antagonists. WO2005/
€
097118, October 20, 2005. (c) Barfacker, L.; Kolkhof, P.; Schlemmer,
K.-H.; Grosser, R.; Nitsche, A.; Klein, M.; M€unter, K.; Albrecht-
K€upper, B.; Hartmann, E. Substituted 4-Aryl-1,4-dihydro-1,6-
naphthyridinamides and Use Thereof. WO2008/104306, September
4, 2008. (d) Arhancet, G. B.; Woodard, S. S.; Dietz, J. D.; Garland, D. J.;
Wagner, G. M.; Iyanar, K.; Collins, J. T.; Blinn, J. R.; Numann, R. E.;
Hu, X.; Huang, H.-C. Stereochemical Requirements for the Mineralo-
corticoid Receptor Antagonist Activity of Dihydropyridines. J. Med.
Chem. 2010, 53, 4300–4304. (e) Arhancet, G. B.; Woodard, S. S.;
Iyanar, K.; Case, B. L.; Woerndle, R.; Dietz, J. D.; Garland, D. J.;
Collins, J. T.; Payne, M. A.; Blinn, J. R.; Pomposiello, S. I.; Hu, X.;
Heron, M. I.; Huang, H.-C.; Lee, L. F. Discovery of Novel Cyanodihy-
dropyridines as Potent Mineralocorticoid Receptor Antagonists.
J. Med. Chem. DOI: 10.1021/jm100506y.
(10) For examples, see the following: (a) Zhang, X.; Li, X.; Allan, G. F.;
Sbriscia, T.; Linton, O.; Lundeen, S. G.; Sui, Z. Design, synthesis,
and in vivo SAR of a novel series of pyrazolines as potent selective
androgen receptor modulators. J. Med. Chem. 2007, 50, 3857–
3869. (b) Zhang, X.; Li, X.; Allan, G. F.; Sbriscia, T.; Linton, O.;
Lundeen, S. G.; Sui, Z. Serendipitous discovery of novel imidazolopyr-
azole scaffold as selective androgen receptor modulators. Bioorg. Med.
Chem. Lett. 2007, 17, 439–443. (c) Jones, D. G.; Liang, X.; Stewart,
E. L.; Noe, R. A.; Kallander, L. S.; Madauss, K. P.; Williams, S. P.;
Thompson, S. K.; Gray, D. W.; Hoekstra, W. J. Discovery of non-
steroidal mifepristone mimetics: pyrazoline-based PR antagonists.
Bioorg. Med. Chem. Lett. 2005, 15, 3203–3206. (d) Combs, D. W.;
Reese, K.; Cornelius, L. A. M.; Gunnet, J. W.; Cryan, E. V.; Granger,
K. S.; Jordan, J. J.; Demarest, K. T. Nonsteroidal progesterone receptor
ligands. 2. High-affinity ligands with selectivity for bone cell proges-
terone receptors. J. Med. Chem. 1995, 38, 4880–4884. (e) Stauffer, S. R.;
Huang, Y. R.; Aron, Z. A.; Coletta, C. J.; Sun, J.; Katzenellenbogen,
B. S.; Katzenellenbogen, J. A. Triarylpyrazoles with basic side chains:
development of pyrazole-based estrogen receptor antagonists. Bioorg.
Med. Chem. 2001, 9, 151–161.
(11) (a) Dahl, L. K.; Heine, M.; Tassinari, L. Effects of chronic excess
salt ingestion. Evidence that genetic factors play an important role
in susceptibility to experimental hypertension. J. Exp. Med. 1962,
115, 1173–1190. (b) Meyers, M. J.; Arhancet, G. B.; Chen, X.;
Hockerman, S. L.; Long, S. A.; Mahoney, M. W.; Reitz, D. B.; Rico,
J. G. Pyrazoline Compounds as Mineralocorticoid Receptor Antago-
nists. WO 2008/053300, May 8, 2008.
(12) Hultman, M. L.; Krasnoperova, N. V.; Li, S.; Du, S.; Xia, C.;
Dietz, J. D.; Lala, D. S.; Welsch, D. J.; Hu, X. The ligand-
dependent interaction of mineralocorticoid receptor with coacti-
vator and corepressor peptides suggests multiple activation mecha-
nisms. Mol. Endocrinol. 2005, 19, 1460–1473.
(20) Bledsoe, R. K.; Madauss, K. P.; Holt, J. A.; Apolito, C. J.;
Lambert, M. H.; Pearce, K. H.; Stanley, T. B.; Stewart, E. L.;
Trump, R. P.; Willson, T. M.; Williams., S. P. A ligand-mediated
hydrogen bond network required for the activation of the miner-
alocorticoid receptor. J. Biol. Chem. 2005, 280, 31283–31293.
(21) Collins, P. W.; Gasiecki, A. F.; Perkins, W. E.; Gullikson, G. W.;
Jones, P. H.; Bauer, R. F. 18-Cycloalkyl analogues of enisoprost.
J. Med. Chem. 1989, 32, 1001–1006.
(13) Powers, D. G.; Casebier, D. S.; Fokas, D.; Ryan, W. J.; Troth,
J. R.; Coffen, D. L. Automated parallel synthesis of chalcone-
based screening libraries. Tetrahedron 1998, 54, 4085.
(14) (a) Bach, K. K.; El-Seedi, H. R.; Jensen, H. M.; Nielsen, H. B.;
Thomsen, I.; Torssell, K. B. G. 1,3-Dipolar cycloadditions of
ethoxycarbonyl-nitrile benzylimine, EtOOCtCNþ-N-CH2C6H5,
and synthesis of β-amino acids. Synthesis and reactions of ethyl
2-chloro-2-ethoxyacetate and 2-chloro-2-ethoxyacetyl chloride. Tet-
rahedron 1994, 50, 7543–7556. (b) For a general review of nitrilimine
cycloadditions, see the following: 1,3-Dipolar Cycloaddition Chemistry;
(22) Koch, K.; Biggers, M. S. General preparation of 7-substituted
4-chromanones: synthesis of a potent aldose reductase inhibitor.
J. Org. Chem. 1994, 59, 1216–1218.
(23) Rodrıguez-Iturbe, B.; Ferrebuz, A.; Vanegas, V.; Quiroz, Y.;
´
Espinoza, F.; Pons, H.; Vaziri, N. D. Early treatment with cGMP
phosphodiesterase inhibitor ameliorates progression of renal da-
mage. Kidney Int. 2005, 68, 2131–2142.
(24) Sherman, W.; Day, T.; Jacobson, M. P.; Friesner, R. A.; Farid, R.
Novel procedure for modeling ligand/receptor induced fit effects.
J. Med. Chem. 2006, 49, 534–553.