Novel and selective calcitonin-inducing agents

A series of xanthine sulfonamides is presented as a class of calcitonin (CT ) inducers - a potentially new method for treating diseases associated with postmenopausal bone loss such as osteoporosis. We have found that certain di-n-butylxanthine sulfonamides 4 upregulate CT transcription in a CT-lucif erase reporter gene assay (CT-luci) and increase the production and release of CT in a CT secretion/RIA assay (CTS). In addition, these compounds do n ot have potent PDE4 inhibitory activity as do the related xanthine methylen e ketones such as denbufyllene (2). One compound in particular (9) shows a transcription activation ratio (TAR) of 2.1 in CT-luci, a CTS increase of 3 .6-fold, and a PDE4 (phosphodiesterase type IV) IC50 = 4.1 mu M. In additio n, this compound showed a statistically significant 47% trabecular bone pro tection in ovariectomized-induced osteopenia (OVX) rats as determined by as say when administered for 4 weeks at 30 mg/kg/day, i.p. by quantitative com puted tomography (QCT). When administered p.o., compound 9 shows 50% trabec ular bone protection when administered for 3 weeks at 50 mg/kg/day, i.p. Th is compared with salmon CT which shows 62% trabecular bone protection when administered at 50 IU/kg/day for 4 weeks.