title: JTT-305, an orally active calcium-sensing receptor antagonist, stimulates transient parathyroid hormone release and bone formation in ovariectomized rats.
abstract: Intermittent administration of parathyroid hormone (PTH) has a potent anabolic effect on bone in humans and animals. Calcium-sensing receptor (CaSR) antagonists stimulate endogenous PTH secretion through CaSR on the surface of parathyroid cells and thereby may be anabolic agents for osteoporosis. JTT-305 is a potent oral short-acting CaSR antagonist and transiently stimulates endogenous PTH secretion. The objective of the present study was to investigate the effects of JTT-305 on PTH secretion and bone in ovariectomized rats. Female rats, immediately after ovariectomy (OVX), were orally administered vehicle or JTT-305 (0.3, 1, or 3 mg/kg) for 12 weeks. The serum PTH concentrations were transiently elevated with increasing doses of JTT-305. In the proximal tibia, JTT-305 prevented OVX-induced decreases in both the cancellous and total bone mineral density (BMD) except for the 0.3mg/kg dose. At the 3mg/kg dose, JTT-305 increased the mineralizing surface and bone formation rate in histomorphometry. The efficacy of JTT-305 at the 3mg/kg dose on the BMD corresponded to that of exogenous rat PTH1-84 injection at doses between 3 and 10 μg/kg. In conclusion, JTT-305 stimulated endogenous transient PTH secretion and bone formation, and consequently prevented bone loss in OVX rats. These results suggest that JTT-305 is orally active and has the potential to be an anabolic agent for the treatment of osteoporosis.
authors.affiliation: Biological/Pharmaceutical Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Osaka, Japan. shuichi.kimura@jt.com
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kimura
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Yushi
authors.initials: Y
authors.lastname: Matsuo
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishida
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Mikio
authors.initials: M
authors.lastname: Hayashi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D019556:COS Cells; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000378:metabolism*; D011412:Propanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D001565:Benzoates; C568849:JTT 305; D010281:Parathyroid Hormone; D011412:Propanolamines; D044169:Receptors, Calcium-Sensing; D011994:Recombinant Proteins