title: A novel calcium-sensing receptor antagonist transiently stimulates parathyroid hormone secretion in vivo.
abstract: Circulating calcium (Ca(2+)) is a primary regulator of bone homeostasis through its action on PTH secretion. Extracellular Ca(2+) 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 IC(50) values of 64 nm and 230 nm in inhibiting intracellular Ca(2+) 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.
authors.affiliation: Metabolic and Cardiovascular Drug Discovery, Bristol-Myers Squibb Co., 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08534, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Arey
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Ma
authors.forename: Aberra
authors.initials: A
authors.lastname: Fura
authors.forename: Jennifer
authors.initials: J
authors.lastname: Morin
authors.forename: Joann
authors.initials: J
authors.lastname: Swartz
authors.forename: Viral
authors.initials: V
authors.lastname: Vyas
authors.forename: Wu
authors.initials: W
authors.lastname: Yang
authors.forename: John K
authors.initials: JK
authors.lastname: Dickson
authors.forename: Jean H M
authors.initials: JH
authors.lastname: Feyen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D010024:Osteoporosis / Q000188:drug therapy; D010281:Parathyroid Hormone / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*
chemical_list: C436740:N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine; D009281:Naphthalenes; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D002118:Calcium