title: 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.affiliation: Amgen Inc., Thousand Oaks, California 91320, USA. david.st.jean@amgen.com
authors.forename: Steve F
authors.initials: SF
authors.lastname: Poon
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
authors.forename: Paul E
authors.initials: PE
authors.lastname: Harrington
authors.forename: Charles
authors.initials: C
authors.lastname: Henley
authors.forename: James
authors.initials: J
authors.lastname: Davis
authors.forename: Sean
authors.initials: S
authors.lastname: Morony
authors.forename: Fred D
authors.initials: FD
authors.lastname: Lott
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Reagan
authors.forename: Jenny Ying-Lin
authors.initials: JY
authors.lastname: Lu
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Yang
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy; D008297:Male; D008744:Methylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010281:Parathyroid Hormone / Q000097:blood; D010627:Phenethylamines; D011437:Propylamines; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000814:Aniline Compounds; D008744:Methylamines; C107873:N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine; D010281:Parathyroid Hormone; D010627:Phenethylamines; D011437:Propylamines; D011720:Pyrazoles; D044169:Receptors, Calcium-Sensing