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

我们以前开发了新的黄嘌呤衍生物具有选择性PDE IV抑制活性，并建议他们表现出成骨细胞和α 1-破骨细胞的行动。本课题致力于进一步开发新的抗骨质疏松药物和骨质疏松动物模型，取得了以下成果：1）一种新的杂环稠合嘌呤，3，4-二丙基-4，5，7，8-四氢-3H-咪唑并[1，2-i]嘌呤5-酮（XT-611），其显示出选择性和有效的PDE IV抑制活性而没有呕吐作用，通过对烷基黄嘌呤衍生物的结构和电子性质的分析，开发了一个新化合物[（Asp）6]。2）我们开发的化合物和其他已知的PDE IV抑制剂在体外和体内实验系统中显示出显著的合成代谢作用。3）我们新开发了一个酸性肽[（Asp）6]，4）Walker 256/S乳腺癌可引起大鼠骨质疏松样改变，并异位分泌LH-RH，导致性激素分泌抑制，性周期停止。因此，该肿瘤可能是绝经后骨质疏松症的一种有用的动物模型。

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.