Discovery and Development of Calcimimetic and Calcilytic Compounds.

The extracellular calcium receptor (CaR) is a G protein-coupled receptor (GPCR) and the pivotal molecule regulating systemic Ca homeostasis. The CaR was a challenging target for drug discovery because its physiological ligand is an inorganic ion (Ca) rather than a molecule so there was no structural template to guide medicinal chemistry. Nonetheless, small molecules targeting this receptor were discovered.

Design, new synthesis, and calcilytic activity of substituted 3H-pyrimidin-4-ones.

Design, new synthesis, structure-activity relationship studies and calcium receptor antagonist (calcilytic) properties of novel 3H-pyrimidin-4-ones are described.

3H-Quinazolin-4-ones as a new calcilytic template for the potential treatment of osteoporosis.

Structure-activity relationship studies, focused on identification of the active pharmacophore fragments in a single high-throughput screening calcilytic hit, resulted in the discovery of potent calcium receptor antagonists, substituted 3H-quinazolin-4-ones.

Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl.

Calcimimetic compounds, which activate the parathyroid cell Ca(2+) receptor (CaR) and inhibit parathyroid hormone (PTH) secretion, are under experimental study as a treatment for hyperparathyroidism. This report describes the salient pharmacodynamic properties, using several test systems, of a new calcimimetic compound, cinacalcet HCl. Cinacalcet HCl increased the concentration of cytoplasmic Ca(2+) ([Ca(2+)](i)) in human embryonic kidney 293 cells expressing the human parathyroid CaR.

Chiral synthesis and pharmacological evaluation of NPS 1407: a potent, stereoselective NMDA receptor antagonist.

The stereoselective synthesis and biological activity of NPS 1407 (4a), (S)-(-)-3-amino-1,1-bis(3-fluorophenyl)butane, a potent, stereoselective antagonist of the NMDA receptor, are described. The racemate (4) was found to be active at the NMDA receptor in an in vitro assay, prompting the synthesis of the individual stereoisomers. The S isomer (4a) was found to be 12 times more potent than the R isomer (4b).