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 their effects on the human calcium-sensing receptor are discussed. Pyrazole 15 was shown to be efficacious in a rat in vivo pharmacodynamic model.
Poon
Steve F
SF
Amgen Inc., Thousand Oaks, California 91320, USA. david.st.jean@amgen.com
St Jean
David J
DJ
Harrington
Paul E
PE
Henley
Charles
C
Davis
James
J
Morony
Sean
S
Lott
Fred D
FD
Reagan
Jeff D
JD
Lu
Jenny Ying-Lin
JY
Yang
Yuhua
Y
Fotsch
Christopher
C
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
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