Parathyroid hormone (PTH) plays an essential role in calcium homeostasis by regulating bone resorption, renal calcium excretion, and intestinal calcium absorption. SB-423562 is a novel, short-acting antagonist for calcium-sensing receptor (CaR) that can induce transient PTH release from parathyroid gland. SB-423562 showed a potent in vitro inhibition of CaR-mediated signaling in HEK-293 cells transfected with human CaR (IC50 = 73nM). In rats, SB-423562 was cleared rapidly (89 mL/min/kg) following the i.v. administration and exhibited a short half-life of 0.23h. In preclinical animal models, systemic treatment of SB-423562 following oral administration did not sufficiently induce PTH release due to the poor intestinal absorption and high hepatic extraction of SB-423562. The administration of SB-423557, the ethyl ester precursor of SB-423562, at 15 and 50mg/kg dose-dependently and transiently increased the circulating level of endogenous PTH in rats as compared to the vehicle-treated controls. SB-423557 treatment also resulted in a transient and significant dose-dependent rise (∼10%) in serum Ca2+ at 1 and 2 h post-dose. The transient upregulation of plasma PTH was also observed in dogs (25mg/kg) and monkeys (50mg/kg) following oral administration of SB-423557. The oral administration of SB-423557 (50mg/kg) in ovariectomized rats for 12 weeks significantly increased the bone mineral density (BMD) in lumbar spine, the trabecular BMD of proximal tibia and the endocortical bone formation rate of distal tibia as compared with the controls[2].
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