This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Arey, B. J. Articles by Feyen, J. H. M. Search for Related Content PubMed PubMed Citation Articles by Arey, B. J. Articles by Feyen, J. H. M.

A Novel Calcium-Sensing Receptor Antagonist Transiently Stimulates Parathyroid Hormone Secretion in Vivo

Departments of Osteoporosis and Frailty (B.J.A., R,S., Z.M., J.M., J.S., J.H.M.F.), Metabolism and Pharmacokinetics (A.F., V.V.), and Discovery Chemistry (W.Y., J.K.D.), Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Hopewell, New Jersey 08534

Address all correspondence and requests for reprints to: Jean H. M. Feyen, Ph.D., Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Co., 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534.

Circulating calcium (Ca²⁺) is a primary regulator of bone homeostasis through its action on PTH secretion. Extracellular Ca²⁺ modulates PTH secretion through a cell surface G protein-coupled receptor, the calcium-sensing receptor (CaR). The expression of the CaR suggests a critical role in cellular regulation by calcium in various organs, including parathyroid gland, bone, and kidney. Despite an obvious pharmacological utility for CaR antagonists in the treatment of disease, only a limited number of such classes of compounds exist. We have identified a novel class of small molecules with specific activity at the CaR. This class of compounds is represented by compound 1. It possesses potent antagonist activity at the human CaR with IC₅₀ values of 64 nM and 230 nM in inhibiting intracellular Ca²⁺ flux and inositol phosphate generation in vitro, respectively. When administered to male rats in vivo, compound 1 robustly increased serum PTH levels. The stimulation of PTH secretion was rapid and transient when administered either iv or orally. The pharmacokinetic profile of compound 1 after oral administration revealed that maximal plasma levels of compound were reached within 1 h and the half-life of the compound to be approximately 2 h in rats. These data describe a representative compound of a novel chemical class than previously described allosteric modulators that offer a new avenue for the development of improved treatments of osteoporosis.

This article has been cited by other articles:

				E. F. Nemeth Anabolic Therapy for Osteoporosis: Calcilytics IBMS BoneKEy, June 1, 2008; 5(6): 196 - 208. [Abstract] [Full Text] [PDF]

				A. Rybczynska, A. Lehmann, A. Jurska-Jasko, K. Boblewski, C. Orlewska, H. Foks, and K. Drewnowska Hypertensive effect of calcilytic NPS 2143 administration in rats. J. Endocrinol., October 1, 2006; 191(1): 189 - 195. [Abstract] [Full Text] [PDF]

				J. Hu, J. Jiang, S. Costanzi, C. Thomas, W. Yang, J. H. M. Feyen, K. A. Jacobson, and A. M. Spiegel A Missense Mutation in the Seven-transmembrane Domain of the Human Ca2+ Receptor Converts a Negative Allosteric Modulator into a Positive Allosteric Modulator J. Biol. Chem., July 28, 2006; 281(30): 21558 - 21565. [Abstract] [Full Text] [PDF]

				S. D. Yanofsky, E. S. Shen, F. Holden, E. Whitehorn, B. Aguilar, E. Tate, C. P. Holmes, R. Scheuerman, D. MacLean, M. M. Wu, et al. Allosteric Activation of the Follicle-stimulating Hormone (FSH) Receptor by Selective, Nonpeptide Agonists J. Biol. Chem., May 12, 2006; 281(19): 13226 - 13233. [Abstract] [Full Text] [PDF]