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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Bibliographic Details
Published in:Journal of medicinal chemistry 2009-11, Vol.52 (21), p.6535-6538
Main Authors: 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: Article
Language:English
Subjects:
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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Summary: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