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 investig...

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Veröffentlicht in:	Journal of medicinal chemistry 2009-02, Vol.52 (4), p.1204-1208
Hauptverfasser:	Yang, Wu, Ruan, Zheming, Wang, Yufeng, Van Kirk, Katy, Ma, Zhengping, Arey, Brian J, Cooper, Christopher B, Seethala, Ramakrishna, Feyen, Jean H. M, Dickson, John K
Format:	Artikel
Sprache:	eng
Schlagworte:	Allosteric Regulation Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Drug Discovery Humans Inhibitory Concentration 50 Medical sciences Osteoporosis - drug therapy Parathyroid Hormone - metabolism Pharmacology. Drug treatments Pyridines - chemistry Pyridines - pharmacology Pyrimidines - chemistry Pyrimidines - pharmacology Receptors, Calcium-Sensing - antagonists & inhibitors Solubility Structure-Activity Relationship
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Zusammenfassung:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm801178c