Discovery and optimization of substituted 1-(1-phenyl-1H-pyrazol-3-yl)methanamines as potent and efficacious type II calcimimetics.

Abstract

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.

• Authors: Steve F Poon, David J St Jean Jr, Paul E Harrington, Charles Henley 3rd, James Davis, Sean Morony, Fred D Lott, Jeff D Reagan, Jenny Ying-Lin Lu, Yuhua Yang, Christopher Fotsch
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 21 Pg. 6535-8 (Nov 12 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19835382 (Publication Type: Journal Article)

Chemical References

• Aniline Compounds
• Methylamines
• N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
• Parathyroid Hormone
• Phenethylamines
• Propylamines
• Pyrazoles
• Receptors, Calcium-Sensing

Topics

• Administration, Oral
• Aniline Compounds (chemical synthesis, chemistry, pharmacology)
• Animals
• Biological Availability
• Cell Line
• Crystallography, X-Ray
• Humans
• Hyperparathyroidism, Secondary (drug therapy)
• Male
• Methylamines (chemical synthesis, chemistry, pharmacology)
• Molecular Structure
• Parathyroid Hormone (blood)
• Phenethylamines
• Propylamines
• Pyrazoles (chemical synthesis, chemistry, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Calcium-Sensing (agonists, metabolism)
• Stereoisomerism
• Structure-Activity Relationship