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

• Published in: Journal of medicinal chemistry Vol. 52; no. 21; pp. 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: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.11.2009; Amer Chemical Soc
• 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; Chemistry, Medicinal; Crystallography, X-Ray; Humans; Hyperparathyroidism, Secondary - drug therapy; Life Sciences & Biomedicine; Male; Medical sciences; Methylamines - chemical synthesis; Methylamines - chemistry; Methylamines - pharmacology; Molecular Structure; Parathyroid Hormone - blood; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phenethylamines; Propylamines; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing - agonists; Receptors, Calcium-Sensing - metabolism; Science & Technology; Stereoisomerism; Structure-Activity Relationship; AGENT; CALCIUM-SENSING RECEPTOR; RAT; IDENTIFICATION; CA2+-SENSING RECEPTOR; Agonist; Rat; Extracellular calcium-sensing receptor; Rodentia; In vitro; Biological activity; Optimization; In vivo; Vertebrata; Mammalia; Allosteric regulation; Animal; Chlorine Organic compounds; Pyrazole derivatives; Bromine Organic compounds; Fluorine Organic compounds; Pharmacokinetics; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9012278

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.