6538 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 21
Poon et al.
and the pharmacokinetic profile. This strategy led to the
development of a highly potent, orally bioavailable com-
pound that significantly lowered PTH levels in a rat in vivo
PD model.
(9) Hebert, S. C. Therapeutic use of calcimimetics. Annu. Rev. Med.
2006, 57, 349–364.
(10) Harrington, P. E.; Fotsch, C. Calcium sensing receptor activators:
calcimimetics. Curr. Med. Chem. 2007, 14, 3027–3034.
(11) Wu, W.-N.; McKown, L. A.; Rybczynski, P. J.; Demarest, K. J.
Hepatic biotransformation of the new calcium-mimetic agent,
RWJ-68025, in the rat and in man;API-MS/MS identification
of metabolites. J. Pharm. Pharmacol. 2003, 55, 631–637.
(12) Dauban, P.; Ferry, S.; Faure, H.; Ruat, M.; Dodd, R. H.
N1-Arylsulfonyl-N2-(1-aryl)ethyl-3-phenylpropane-1,2-diamines
as novel calcimimetics acting on the calcium sensing receptor.
Bioorg. Med. Chem. Lett. 2000, 10, 2001–2004.
Acknowledgment. The authors thank Rashid Syed for
providing X-ray crystallographic support, Chris Wilde for
spectroscopic assistance, and Guifen Xu, Jie Chen, Dean
Hickman, Ronya Shatila, Anna Akrami, and Valerie Almon
for pharmacokinetic analysis.
(13) Kessler, A.; Faure, H.; Petrel, C.; Ruat, M.; Dauban, P. M.; Dodd,
R. H. N2-Benzyl-N1-(1-(1-naphthyl)ethyl)-3-phenylpropane-1,
2-diamines and conformationally restrained indole analogues:
development of calindol as a new calcimimetic acting at the
calcium sensing receptor. Bioorg. Med. Chem. Lett. 2004, 14,
3345–3349.
Supporting Information Available: Experimental details,
characterization methods and results, and X-ray crystallo-
graphic data. This material is available free of charge via the
(14) Balfour, J. A. B.; Scott, L. J. Drugs 2005, 65, 271–281.
(15) Nemeth, E. F.; Steffey, M. E.; Hammerland, L. G.; Hung, B. C. P.;
Van Wagenen, B. C.; Del Mar, E. G.; Balandrin, M. F. Calcimi-
metics with potent and selective activity on the parathyroid calcium
receptor. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 4040–4045.
(16) Antonsen, J. E.; Sherrard, D. J.; Andress, D. L. A calcimimetic
agent acutely suppresses parathyroid hormone levels in patients
with chronic renal failure. Kidney Int. 1998, 53, 223–227.
References
(1) Rodriguez, M.; Nemeth, E.; Martin, D. The calcium-sensing
receptor: a key factor in the pathogenesis of secondary hyperpara-
thyroidism. Am. J. Physiol.: Renal Physiol. 2005, 288, F253–F264.
(2) Skorecki, K.; Green, J.; Brenner, B. M. In Harrison’s Principles of
Internal Medicine, 16th ed.; Kaspar, D. L., Braunwald, E., Fauci, A. S.,
Hauser, S. L., Longo, D. L., Jameson, J. L., Eds.; McGraw-Hill: New
York, 2005; Vol. 261, pp 1653-1663.
(3) Slatopolosky, E.; Brown, A.; Dusso, A. Pathogenesis of secondary
hyperparathyroidism. Kidney Int., Suppl. 1999, 73, S14–S19.
(4) Brown, E. M.; Gamba, G.; Riccardi, D.; Lombardi, M.; Butters,
R.; Kifor, O.; Sun, A.; Hediger, M. A.; Lytton, J.; Hebert, S. C.
Cloning and characterization of an extracellular Ca2þ-sensing
receptor from bovine parathyroid. Nature 1993, 366, 575–579.
(5) Brown, E. M.; MacLeod, R. J. Extracellular calcium sensing and
extracellular calcium signaling. Physiol. Rev. 2001, 81, 239–297.
(6) Hu, J.; Reyes-Cruz, G.; Chen, W.; Jackson, K. A.; Spiegel, A. M.
Identification of acidic residues in the extracellular loops of the
seven-transmembrane domain of the human Ca2þ receptor critical
for response to Ca2þ and a positive allosteric modulator. J. Biol.
Chem. 2002, 277, 46622–46631.
~
(17) Frazao, J. M.; Martins, P.; Coburn, J. W. The calcimimetic agents:
perspectives for treatment. Kidney Int. 2002, 61, S149–S154.
(18) Veber, D. F; Johnson, S. R.; Cheng, H. Y.; Smith, B. R.; Ward, K.
W.; Kopple, K. D. Molecular properties that influence the oral
bioavailabilty of drug candidates. J. Med. Chem. 2002, 45, 2615–
2623.
(19) Bringmann, G.; Geisler, J. P. Enantiomerically pure oxygenated
1-phenylethylamines from substituted acetophenones: by reductive
amination and regiospecific benzylic cleavage. Tetrahedron Lett.
1989, 30, 317–320.
(20) In a closely related series, the (R,R)-diastereomer was shown to be
the more active epimer (data not shown).
(21) Holzer, W.; Plagens, B.; Lorenz, K. Alkylation of pyrazolones via
the Mitsunobu reaction. Heterocycles 1997, 45, 309–314.
(22) The PD of cinacalcet in normal rats has been reported: Nemeth,
E. F.; Heaton, W. H.; Miller, M.; Fox, J.; Balandrin, M. F.; Van
Wagenen, B. C.; Colloton, M.; Karbon, W.; Scherrer, J.; Shatzen,
E.; Rishton, G.; Scully, S.; Qi, M.; Harris, R.; Lacey, D.; Martin, D.
Pharmacodynamics of the type II calcimimetic compound cinacal-
cet. J. Pharmacol. Exp. Ther. 2004, 308, 627–635.
(7) Bai, M. Structure and function of the extracellular calcium-sensing
receptors. Int. J. Mol. Med. 1999, 4, 115–125.
(8) Ruat, M.; Snowman, A. M.; Hester, L. D.; Snyder, S. H. Cloned
and expressed rat Ca2þ-sensing receptor. J. Biol. Chem. 1996, 271,
5972–5975.