title: ATF936, a novel oral calcilytic, increases bone mineral density in rats and transiently releases parathyroid hormone in humans.
abstract: Parathyroid hormone (PTH), when injected daily as either the intact hormone PTH(1-84) or the active fragment PTH(1-34) (teriparatide), is an efficacious bone anabolic treatment option for osteoporosis patients. Injections lead to rapid and transient spikes in hormone exposure levels, a profile which is a prerequisite to effectively form bone. Oral antagonists of the calcium-sensing receptor (calcilytics) stimulate PTH secretion and represent thus an alternative approach to elevate hormone levels transiently. We report here on ATF936, a novel calcilytic, which triggered rapid, transient spikes in endogenous PTH levels when given orally in single doses of 10 and 30mg/kg to growing rats, and of 1mg/kg to dogs. Eight weeks daily oral application of 30mg/kg of ATF936 to aged female rats induced in the proximal tibia metaphysis increases in bone mineral density, cancellous bone volume and cortical and trabecular thickness as evaluated by computed tomography. In healthy humans, single oral doses of ATF936 produced peak PTH levels in plasma after a median time of 1h and levels returned to normal at 24-h post-dose. The average maximum PTH concentration increase from baseline was 1.9, 3.6, and 6.0-fold at doses of 40, 70, and 140mg. ATF936 was well tolerated. The sharp, transient increase in PTH levels produced by the oral calcilytic ATF936 was comparable to the PTH profile observed after subcutaneous administration of teriparatide. In conclusion, ATF936 might hold potential as an oral bone-forming osteoporosis therapy.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. markus.john@novartis.com
authors.forename: Markus R
authors.initials: MR
authors.lastname: John
authors.forename: Leo
authors.initials: L
authors.lastname: Widler
authors.forename: Rainer
authors.initials: R
authors.lastname: Gamse
authors.forename: Thomas
authors.initials: T
authors.lastname: Buhl
authors.forename: Klaus
authors.initials: K
authors.lastname: Seuwen
authors.forename: Werner
authors.initials: W
authors.lastname: Breitenstein
authors.forename: Gerard J M
authors.initials: GJ
authors.lastname: Bruin
authors.forename: Rossella
authors.initials: R
authors.lastname: Belleli
authors.forename: Lloyd B
authors.initials: LB
authors.lastname: Klickstein
authors.forename: Michaela
authors.initials: M
authors.lastname: Kneissel
mesh_terms: D000328:Adult; D045930:Anabolic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D005260:Female; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010281:Parathyroid Hormone / Q000378:metabolism* / Q000494:pharmacology*; D052999:Quinazolinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*
chemical_list: C000604141:ATF936; D045930:Anabolic Agents; D010281:Parathyroid Hormone; D052999:Quinazolinones; D044169:Receptors, Calcium-Sensing; D002118:Calcium