Metabolism-guided discovery of a potent and orally bioavailable urea-based calcimimetic for the treatment of secondary hyperparathyroidism.
A series of urea based calcimimetics was optimized for potency and oral bioavailability. Crucial to this process was overcoming the poor pharmacokinetic properties of lead thiazole 1. Metabolism-guided modifications, characterized by the use of metabolite identification (ID) and measurement of time dependent inhibition (TDI) of CYP3A4, were essential to finding a compound suitable for oral dosing. Calcimimetic 18 exhibited excellent in vivo potency in a 5/6 nephrectomized rat model and cross-species pharmacokinetics.
Department of Medicinal Chemistry, Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA.
Paul M
PM
Wehn
Paul E
PE
Harrington
Timothy J
TJ
Carlson
James
J
Davis
Pierre
P
Deprez
Christopher H
CH
Fotsch
Mark P
MP
Grillo
Jenny Ying-Lin
JY
Lu
Sean
S
Morony
Kanaka
K
Pattabiraman
Steve F
SF
Poon
Jeff D
JD
Reagan
David J
DJ
St Jean
Taoues
T
Temal
Minghan
M
Wang
Yuhua
Y
Yang
Charles
C
Henley
Sarah E
SE
Lively
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006207:Half-Life; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010281:Parathyroid Hormone / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000737:chemistry / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014508:Urea / Q000031:analogs & derivatives*
D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D013844:Thiazoles; D014508:Urea
1,2,4-Thiadiazoles; Calcimimetics; Metabolite ID; Positive allosteric modulators; Time dependent inhibition