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

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...