Basic Studies for development of anti-osteoporosis drugs from PDEIV inhibitors.

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We previously developed new xanthine derivatives having selective PDE IV inhibitory activity, and suggested that they exhibited osteoblastogenic and a1ti- osteoclastogenic actions. We attemped to further develop new anti-osteoporosis drugs arid osteoporosis animal model in the research project and obtained the following results ;1)A new heterocycle-condensed purine, 3 , 4-dipropyl-4, 5,7, 8-tetrahydro-3H-imidazo [l, 2-i]purin 5-one (XT-611), which shows selective and potent PDE lV inhibitory activity without emetic action, was developed according to the analysis of the structural and electronic properties of alkylxanthine derivatives.2)Our developed compounds and other known PDE IV inhibitors showed significant anabolic actions in the in vitro and in viva experimental systems.3)We newly developed an acidic peptide [(Asp)6], which was a good carrier of drug for bone targeting.4)We showed that Walker256/S mammary carcinoma caused osteoporisis-like changes in rats and ectopically secreted LH-RH, resulting inhibition of sex hormone secretion and stopping the sex cycle. Then, this tumor may be a useful animal model for postmenopausal osteoprosis.