title: Discovery and structure-activity relationships of trisubstituted pyrimidines/pyridines as novel calcium-sensing receptor antagonists.
abstract: 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.
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. Wu.Yang@bms.com
authors.forename: Wu
authors.initials: W
authors.lastname: Yang
authors.forename: Zheming
authors.initials: Z
authors.lastname: Ruan
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Katy
authors.initials: K
authors.lastname: Van Kirk
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Ma
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Arey
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Cooper
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Jean H M
authors.initials: JH
authors.lastname: Feyen
authors.forename: John K
authors.initials: JK
authors.lastname: Dickson
mesh_terms: 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
chemical_list: D010281:Parathyroid Hormone; D011725:Pyridines; D011743:Pyrimidines; D044169:Receptors, Calcium-Sensing