Discovery and structure-activity relationships of trisubstituted pyrimidines/pyridines as novel calcium-sensing receptor antagonists.
The trisubstituted pyrimidine 1 was identified through high-throughput screening as a novel calcium-sensing receptor (CaSR) antagonist. Small molecule CaSR antagonists and/or negative allosteric modulators have the potential to act as an anabolic agent for the treatment of osteoporosis. The investigation of structure-activity relationships around 1 resulted in the identification of 18c and 18d, which showed efficacy at promoting PTH release in vivo and exhibited improved potency and solubility over the original lead 1.
Yang
Wu
W
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. Wu.Yang@bms.com
Ruan
Zheming
Z
Wang
Yufeng
Y
Van Kirk
Katy
K
Ma
Zhengping
Z
Arey
Brian J
BJ
Cooper
Christopher B
CB
Seethala
Ramakrishna
R
Feyen
Jean H M
JH
Dickson
John K
JK
D000494:Allosteric Regulation; D055808:Drug Discovery; D006801:Humans; D020128:Inhibitory Concentration 50; D010024:Osteoporosis / Q000188:drug therapy; D010281:Parathyroid Hormone / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship
D010281:Parathyroid Hormone; D011725:Pyridines; D011743:Pyrimidines; D044169:Receptors, Calcium-Sensing