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Novel and selective calcitonin-inducing agents
A M Gilbert1, S Caltabiano, D Roberts
1Chemical Sciences, Wyeth-Ayerst Research, 401 North Middletown Road, Pearl River, New York 10965-1299, USA. gilbera@war.wyeth.com
Abstract:
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-luciferase 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 not have potent PDE4 inhibitory activity as do the related xanthine methylene 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) IC(50) = 4.1 microM. In addition, this compound showed a statistically significant 47% trabecular bone protection in ovariectomized-induced osteopenia (OVX) rats as determined by assay when administered for 4 weeks at 30 mg/kg/day, i. p. by quantitative computed tomography (QCT). When administered p.o., compound 9 shows 50% trabecular bone protection when administered for 3 weeks at 50 mg/kg/day, i.p. This compared with salmon CT which shows 62% trabecular bone protection when administered at 50 IU/kg/day for 4 weeks.
Insights
New xanthine sulfonamides can induce calcitonin (CT) production, offering a potential treatment for osteoporosis and postmenopausal bone loss. These compounds effectively increase CT levels without significant PDE4 inhibition.
Area of Science:
- Pharmacology
- Endocrinology
- Bone Biology
Background:
- Osteoporosis is a significant health concern, particularly after menopause.
- Current treatments for bone loss have limitations.
- Calcitonin (CT) plays a role in bone metabolism.
Purpose of the Study:
- To identify novel compounds that can induce calcitonin (CT) production.
- To evaluate the potential of these compounds as a new therapeutic strategy for osteoporosis.
Main Methods:
- Synthesis and screening of xanthine sulfonamides.
- Utilized CT-luciferase reporter gene assay (CT-luci) to measure CT transcription.
- Employed CT secretion/RIA assay (CTS) to assess CT production and release.
- Evaluated phosphodiesterase type IV (PDE4) inhibitory activity.
- Assessed bone protection in ovariectomized (OVX) rats using quantitative computed tomography (QCT).
Main Results:
- Certain di-n-butylxanthine sulfonamides upregulated CT transcription and increased CT production/release.
- Compound 9 demonstrated a 2.1-fold transcription activation ratio and a 3.6-fold increase in CT secretion.
- Compound 9 showed significant trabecular bone protection (47-50%) in OVX rats, with minimal PDE4 inhibition (IC50 = 4.1 microM).
- Efficacy compared favorably to salmon CT in preclinical models.
Conclusions:
- Xanthine sulfonamides represent a promising class of CT inducers.
- These compounds offer a potential new therapeutic avenue for treating postmenopausal bone loss and osteoporosis.
- Compound 9 warrants further investigation as a potential drug candidate.