Discovery and Optimization of Substituted 1-(1-Phenyl-1H-pyrazol-3-yl)methanamines as Potent and Efficacious Type II Calcimimetics

Our efforts to discover potent, orally bioavailable type II calcimimetic agents for the treatment of secondary hyperparathyroidism focused on the development of ring constrained analogues of the known calcimimetic R-568. The structure−activity relationships of various substituted heterocycles and th...

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Veröffentlicht in:	Journal of medicinal chemistry 2009-11, Vol.52 (21), p.6535-6538
Hauptverfasser:	Poon, Steve F, St. Jean, David J, Harrington, Paul E, Henley, Charles, Davis, James, Morony, Sean, Lott, Fred D, Reagan, Jeff D, Lu, Jenny Ying-Lin, Yang, Yuhua, Fotsch, Christopher
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Aniline Compounds - chemical synthesis Aniline Compounds - chemistry Aniline Compounds - pharmacology Animals Biological and medical sciences Biological Availability Bones, joints and connective tissue. Antiinflammatory agents Cell Line Crystallography, X-Ray Humans Hyperparathyroidism, Secondary - drug therapy Male Medical sciences Methylamines - chemical synthesis Methylamines - chemistry Methylamines - pharmacology Molecular Structure Parathyroid Hormone - blood Pharmacology. Drug treatments Phenethylamines Propylamines Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Rats Rats, Sprague-Dawley Receptors, Calcium-Sensing - agonists Receptors, Calcium-Sensing - metabolism Stereoisomerism Structure-Activity Relationship
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Zusammenfassung:	Our efforts to discover potent, orally bioavailable type II calcimimetic agents for the treatment of secondary hyperparathyroidism focused on the development of ring constrained analogues of the known calcimimetic R-568. The structure−activity relationships of various substituted heterocycles and their effects on the human calcium-sensing receptor are discussed. Pyrazole 15 was shown to be efficacious in a rat in vivo pharmacodynamic model.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm9012278