Short-acting 5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as orally-active calcium-sensing receptor antagonists.
Synthesis and structure-activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.
Didiuk
Mary T
MT
Pfizer Global Research and Development, Groton, CT 06340, United States. mary.didiuk@pfizer.com
Griffith
David A
DA
Benbow
John W
JW
Liu
Kevin K C
KK
Walker
Daniel P
DP
Bi
F Christopher
FC
Morris
Joel
J
Guzman-Perez
Angel
A
Gao
Hua
H
Bechle
Bruce M
BM
Kelley
Ryan M
RM
Yang
Xiaojing
X
Dirico
Kenneth
K
Ahmed
Syed
S
Hungerford
William
W
DiBrinno
Joseph
J
Zawistoski
Michael P
MP
Bagley
Scott W
SW
Li
Jianke
J
Zeng
Yuan
Y
Santucci
Stephanie
S
Oliver
Robert
R
Corbett
Matthew
M
Olson
Thanh
T
Chen
Chiliu
C
Li
Mei
M
Paralkar
Vishwas M
VM
Riccardi
Keith A
KA
Healy
David R
DR
Kalgutkar
Amit S
AS
Maurer
Tristan S
TS
Nguyen
Hang T
HT
Frederick
Kosea S
KS
D000284:Administration, Oral; D045930:Anabolic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D008297:Male; D010281:Parathyroid Hormone / Q000378:metabolism; D011744:Pyrimidinones / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D045930:Anabolic Agents; D010281:Parathyroid Hormone; D011744:Pyrimidinones; D044169:Receptors, Calcium-Sensing